ACIR Journal Articles

New soluble CSF-1R-dimeric mutein with enhanced trapping of both CSF-1 and IL-34 reduces suppressive tumor-associated macrophages in pleural mesothelioma Spotlight

(1) Joalland N (2) Quéméner A (3) Deshayes S (4) Humeau R (5) Maillasson M (6) LeBihan H (7) Salama A (8) Fresquet J (9) Remy S (10) Mortier E (11) Blanquart C (12) Guillonneau C (13) Anegon I

Journal for immunotherapy of cancer - Open Access | Free PMC Article

To inhibit interactions of CSF-1 with CSF-1R and IL-34 with CSF-1R, PTPζ, SDC-1 and TREM2, Joalland et al. generated a soluble fusion protein comprising a mutein (M149K) of the human CSF-1R extracellular domain dimerized by a silenced human IgG1Fc. Mutein CSF-1R-Fc had higher affinity for CSF-1 and IL-34 than wild-type CSF-1R-Fc; inhibited CSF-1R signaling, monocyte viability, and induction of suppressive TAMs by CSF-1/IL-34-expressing pleural mesothelioma cells better than anti-IL-34 and/or anti-CSF-1 mAbs; and induced lysis of mesothelioma cells by a tumor-specific CD8+ T cell clone in mesothelioma/macrophage spheroids in vitro and in vivo.

Contributed by Paula Hochman

(1) Joalland N (2) Quéméner A (3) Deshayes S (4) Humeau R (5) Maillasson M (6) LeBihan H (7) Salama A (8) Fresquet J (9) Remy S (10) Mortier E (11) Blanquart C (12) Guillonneau C (13) Anegon I

Journal for immunotherapy of cancer - Open Access | Free PMC Article

To inhibit interactions of CSF-1 with CSF-1R and IL-34 with CSF-1R, PTPζ, SDC-1 and TREM2, Joalland et al. generated a soluble fusion protein comprising a mutein (M149K) of the human CSF-1R extracellular domain dimerized by a silenced human IgG1Fc. Mutein CSF-1R-Fc had higher affinity for CSF-1 and IL-34 than wild-type CSF-1R-Fc; inhibited CSF-1R signaling, monocyte viability, and induction of suppressive TAMs by CSF-1/IL-34-expressing pleural mesothelioma cells better than anti-IL-34 and/or anti-CSF-1 mAbs; and induced lysis of mesothelioma cells by a tumor-specific CD8+ T cell clone in mesothelioma/macrophage spheroids in vitro and in vivo.

Contributed by Paula Hochman

BACKGROUND: Colony stimulating factor-1 receptor (CSF-1R) and its ligands CSF-1 and interleukin (IL)-34 have tumorigenic effects through both induction of suppressive macrophages, and survival/proliferation of tumor cells. In addition, the IL-34 tumorigenic effect can also be mediated by its other receptors, protein-tyrosine phosphatase zeta, Syndecan-1 (CD138) and triggering receptor expressed on myeloid cells 2. Small tyrosine kinase inhibitors are used to block CSF-1R signaling but lack specificity. Neutralizing anti-CSF-1 and/or IL-34 antibodies have been proposed, but their effects are limited. Thus, there is a need for a more specific and yet integrative approach. METHODS: A human mutated form of the extracellular portion of CSF-1R was in silico modelized to trap both IL-34 and CSF-1 with higher affinity than the wild-type CSF-1R by replacing the methionine residue at position 149 with a Lysine ((M149K)). The extracellular portion of the mutated CSF-1R M149K was dimerized using the immunoglobulin Fc sequence of a silenced human IgG1 (sCSF-1R(M149K)-Fc). Signaling through CSF-1R, survival of monocytes and differentiation of suppressive macrophages were analyzed using pleural mesothelioma patient's samples and mesothelioma/macrophage spheroids in vitro and in vivo in the presence of sCSF-1R(M149K)-Fc or sCSF-1R-Fc wild type control (sCSF-1R(WT)-Fc). RESULTS: We defined that the D1 to D5 domains of the extracellular portion of CSF-1R were required for efficient binding to IL-34 and CSF-1. The mutein sCSF-1R(M149K)-Fc trapped with higher affinity than sCSF-1R(WT)-Fc both CSF-1 and IL-34 added in culture and naturally produced in mesothelioma pleural effusions. sCSF-1R(M149K)-Fc inhibited CSF-1R signaling, survival and differentiation of human suppressive macrophage in vitro and in vivo induced by pleural mesothelioma cells. Neutralization of IL-34 and CSF-1 by sCSF-1R(M149K)-Fc also resulted in higher killing of pleural mesothelioma cells by a tumor-specific CD8(+) T cell clone in mesothelioma/macrophage spheroids. CONCLUSIONS: sCSF-1R(M149K)-Fc efficiently traps both CSF-1 and IL-34 and inhibits CSF-1R signaling, monocyte survival and suppressive macrophage differentiation induced by pleural mesothelioma cells producing CSF-1 and IL-34, as well as restores cytotoxic T-cell responses. sCSF-1R(M149K)-Fc has therapeutic potential vs other therapies under development targeting single components of this complex cytokine pathway involved in cancer.

Author Info: (1) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes Universit, Nantes, France. (2) LabE

Author Info: (1) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes Universit, Nantes, France. (2) LabEx IGO, Nantes Universit, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, Universit d'Angers, CRCI2NA, University of Nantes, Nantes, France. (3) LabEx IGO, Nantes Universit, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, Universit d'Angers, CRCI2NA, University of Nantes, Nantes, France. (4) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes Universit, Nantes, France. (5) LabEx IGO, Nantes Universit, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, Universit d'Angers, CRCI2NA, University of Nantes, Nantes, France. INSERM, CNRS, SFR Bonamy, UMS BioCore, Imp@ct Platform, Nantes Universit, Centre Hospitalo-Universitaire (CHU) Nantes, Nantes, France. (6) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes Universit, Nantes, France. (7) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. LabEx IGO, Nantes Universit, Nantes, France. (8) LabEx IGO, Nantes Universit, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, Universit d'Angers, CRCI2NA, University of Nantes, Nantes, France. (9) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France. (10) LabEx IGO, Nantes Universit, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, Universit d'Angers, CRCI2NA, University of Nantes, Nantes, France. INSERM, CNRS, SFR Bonamy, UMS BioCore, Imp@ct Platform, Nantes Universit, Centre Hospitalo-Universitaire (CHU) Nantes, Nantes, France. (11) LabEx IGO, Nantes Universit, Nantes, France. INSERM, UMR 1307, CNRS UMR 6075, Universit d'Angers, CRCI2NA, University of Nantes, Nantes, France. (12) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France ianegon@nantes.inserm.fr carole.guillonneau@univ-nantes.fr. LabEx IGO, Nantes Universit, Nantes, France. (13) INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France ianegon@nantes.inserm.fr carole.guillonneau@univ-nantes.fr. LabEx IGO, Nantes Universit, Nantes, France.

Citation: J Immunother Cancer 2025 Mar 17 13: Epub03/17/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40101804

Tags:

Embryonic reprogramming of the tumor vasculature reveals targets for cancer therapy Spotlight

(1) Huijbers EJM (2) van Beijnum JR (3) van Loon K (4) Griffioen CJ (5) Volckmann R (6) Bassez A (7) Lambrechts D (8) Nunes Monteiro M (9) Jimenez CR (10) Hogendoorn PCW (11) Koster J (12) Griffioen AW

Proceedings of the National Academy of Sciences of the United States of America

Hypothesizing that tumor endothelial cells (TECs) re-express fetal genes in tumor tissues, Huijbers et al. identified target genes selectively expressed in mouse embryos and in sorted TECs, but not in adult mice. Identified TEC self-antigens (Fbn2, Emilin2, Lox and Pai-1) were validated in in vitro angiogenesis assays and were used to generate fusion protein vaccines (with bacterial thioredoxin) that induced highly specific polyclonal Abs and inhibited tumor growth in preclinical models, without affecting healthy vasculature (Fbn2 and Emilin2 vaccines). High levels of FBN2 and EMILIN2 correlated with elevated levels of ECs in human CRC and melanoma.

Contributed by Katherine Turner

(1) Huijbers EJM (2) van Beijnum JR (3) van Loon K (4) Griffioen CJ (5) Volckmann R (6) Bassez A (7) Lambrechts D (8) Nunes Monteiro M (9) Jimenez CR (10) Hogendoorn PCW (11) Koster J (12) Griffioen AW

Proceedings of the National Academy of Sciences of the United States of America

Hypothesizing that tumor endothelial cells (TECs) re-express fetal genes in tumor tissues, Huijbers et al. identified target genes selectively expressed in mouse embryos and in sorted TECs, but not in adult mice. Identified TEC self-antigens (Fbn2, Emilin2, Lox and Pai-1) were validated in in vitro angiogenesis assays and were used to generate fusion protein vaccines (with bacterial thioredoxin) that induced highly specific polyclonal Abs and inhibited tumor growth in preclinical models, without affecting healthy vasculature (Fbn2 and Emilin2 vaccines). High levels of FBN2 and EMILIN2 correlated with elevated levels of ECs in human CRC and melanoma.

Contributed by Katherine Turner

ABSTRACT: A sustained blood supply is critical for tumor growth, as it delivers the nutrients and oxygen required for development. Targeting of blood vessel formation via immunotherapies is an area of great importance. Knowing that certain embryonic genes, such as carcinoembryonic antigens (CEA) and oncofetal fibronectin, become reexpressed in malignant transformation, we hypothesized that a similar phenomenon holds true for tumor endothelial cells (TECs) as well. An approach for identification of highly selective tumor endothelial markers was conducted to develop targeted antiangiogenic immunotherapies. We first queried the transcriptome that is present during embryo development. We then performed a systematic search for genes selectively expressed in the mouse embryo at days E11 and E18, as compared to the transcriptome of the adult mouse. Subsequently, we queried for expression of these embryonic genes in sorted murine TECs. This approach identified among others the tumor endothelial antigens fibrillin-2 (Fbn2), elastin microfibril interface-located protein 2 (Emilin2) as well as the tumor endothelial antigens lysyl oxidase (Lox) and serine/cysteine protease inhibitor, clade E, member 1 (Serpine1; Pai-1). For these selected genes, functional involvement in angiogenesis was confirmed in in vitro bioassays. We subsequently used iBoost conjugate vaccine technology to develop vaccines against the selected targets. For all four targets, vaccination readily induced target-specific antibody responses in mice, resulting in inhibition of tumor growth. Access to highly specific tumor endothelial markers provides opportunities for direct targeting of the tumor vasculature with high specificity, without affecting healthy vasculature.

Author Info: (1) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. CimCure Besloten Venn

Author Info: (1) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. CimCure Besloten Vennootschap, Amsterdam 1066 CX, The Netherlands. (2) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. (3) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. (4) Laboratory of Experimental Oncology and Radiobiology, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1105 AZ, The Netherlands. (5) Laboratory of Experimental Oncology and Radiobiology, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1105 AZ, The Netherlands. (6) Vlaams Instituut voor Biotechnologie-Katolieke Universiteit Leuven Center for Cancer Biology, Leuven 3000, Belgium. (7) Vlaams Instituut voor Biotechnologie-Katolieke Universiteit Leuven Center for Cancer Biology, Leuven 3000, Belgium. (8) Department of Medical Oncology, Oncoproteomics Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. (9) Department of Medical Oncology, Oncoproteomics Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. (10) Department of Pathology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands. (11) Laboratory of Experimental Oncology and Radiobiology, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1105 AZ, The Netherlands. (12) Department of Medical Oncology, Angiogenesis Laboratory, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam 1081 HV, The Netherlands. CimCure Besloten Vennootschap, Amsterdam 1066 CX, The Netherlands.

Citation: Proc Natl Acad Sci U S A 2025 Mar 25 122:e2424730122 Epub03/17/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40096611

Tags:

A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells Spotlight

(1) Chen X (2) Tang X (3) Xie Y (4) Cuffari BJ (5) Tang C (6) Cao F (7) Gao X (8) Meng Z (9) Noble PW (10) Young MR (11) Turk OM (12) Shirali A (13) Gera J (14) Nishimura RN (15) Zhou J (16) Hansen JE

Science signaling

Chen et al. found that the guanosine binding autoantibody 4H2 uses nucleoside transporter-2 (ENT-2)-mediated nucleoside transport to penetrate into and localize in the cytoplasm of live cells, thus avoiding endosomes and lysosomes. 4H2 activated and promoted cGAS signaling and cGAS-dependent cytotoxicity in a nucleic acid-dependent interaction, but did not interfere with protein translation. In orthotropic GBM mouse models, systemically administered 4H2 localized to areas of necrotic tumor cells, increased T cell infiltration, and prolonged survival in a T cell-dependent manner. When injected locally, 4H2 delivered functional mRNA to cells.

Contributed by Ute Burkhardt

(1) Chen X (2) Tang X (3) Xie Y (4) Cuffari BJ (5) Tang C (6) Cao F (7) Gao X (8) Meng Z (9) Noble PW (10) Young MR (11) Turk OM (12) Shirali A (13) Gera J (14) Nishimura RN (15) Zhou J (16) Hansen JE

Science signaling

Chen et al. found that the guanosine binding autoantibody 4H2 uses nucleoside transporter-2 (ENT-2)-mediated nucleoside transport to penetrate into and localize in the cytoplasm of live cells, thus avoiding endosomes and lysosomes. 4H2 activated and promoted cGAS signaling and cGAS-dependent cytotoxicity in a nucleic acid-dependent interaction, but did not interfere with protein translation. In orthotropic GBM mouse models, systemically administered 4H2 localized to areas of necrotic tumor cells, increased T cell infiltration, and prolonged survival in a T cell-dependent manner. When injected locally, 4H2 delivered functional mRNA to cells.

Contributed by Ute Burkhardt

ABSTRACT: Nucleic acid-mediated signaling triggers an immune response that is believed to be central to the pathophysiology of autoimmunity in systemic lupus erythematosus (SLE). Here, we found that a cell-penetrating, SLE-associated antiguanosine autoantibody may present therapeutic opportunities for cancer treatment. The autoantibody entered cells through a nucleoside salvage-linked pathway of membrane transit that avoids endosomes and lysosomes and bound to endogenous RNA in live cells. In orthotopic models of glioblastoma, the antibody localized to areas adjacent to necrotic tumor cells and promoted animal survival in a manner that depended on T cells. Mechanistic studies revealed that antibody binding to nucleic acids activated the cytoplasmic pattern recognition receptor cyclic GMP-AMP synthase (cGAS), thereby stimulating immune signaling and cGAS-dependent cytotoxicity. Moreover, the autoantibody could carry and deliver functional RNA into tumor, brain, and muscle tissues in live mice when administered locally. The findings establish a collaborative autoantibody-nucleic acid interaction that is translatable to strategies for nonviral gene delivery and immunotherapy.

Author Info: (1) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (2) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (3) D

Author Info: (1) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (2) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (3) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (4) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (5) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (6) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (7) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (8) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. (9) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (10) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA. (11) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (12) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. (13) Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Johnson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA. Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA. Department of Research & Development, Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA 91343, USA. (14) Department of Research & Development, Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA 91343, USA. Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, CA 90095, USA. (15) Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA. Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA. (16) Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA. Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA.

Citation: Sci Signal 2025 Mar 25 18:eadk3320 Epub03/25/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40132052

Tags:

Translation dysregulation in cancer as a source for targetable antigens Featured

(1) Weller C (2) Bartok O (3) McGinnis CS (4) Palashati H (5) Chang TG (6) Malko D (7) Shmueli MD (8) Nagao A (9) Hayoun D (10) Murayama A (11) Sakaguchi Y (12) Poulis P (13) Khatib A (14) Erlanger Avigdor B (15) Gordon S (16) Cohen Shvefel S (17) Zemanek MJ (18) Nielsen MM (19) Boura-Halfon S (20) Sagie S (21) Gumpert N (22) Yang W (23) Alexeev D (24) Kyriakidou P (25) Yao W (26) Zerbib M (27) Greenberg P (28) Benedek G (29) Litchfield K (30) Petrovich-Kopitman E (31) Nagler A (32) Oren R (33) Ben-Dor S (34) Levin Y (35) Pilpel Y (36) Rodnina M (37) Cox J (38) Merbl Y (39) Satpathy AT (40) Carmi Y (41) Erhard F (42) Suzuki T (43) Buskirk AR (44) Olweus J (45) Ruppin E (46) Schlosser A (47) Samuels Y

Cancer cell - Open Access

Investigating the role of translation dysregulation in antitumor immunity, Weller, Bartok, and McGinnis et al. evaluated the effects of TYW2 – a tRNA transferase that supports reading frame maintenance in ribosomes – and found that loss of TYW2 leads to the expression of aberrant peptides, which are presented by MHC and can be recognized by CD8⁺ T cells, enhancing tumor infiltration and antitumor immune responses. Further, loss of TYW2 enhanced CD8⁺ T cell exhaustion and sensitivity to checkpoint blockade. TYW2 expression leve ls in a population of patients with melanoma predicted clinical responses and survival outcomes.

(1) Weller C (2) Bartok O (3) McGinnis CS (4) Palashati H (5) Chang TG (6) Malko D (7) Shmueli MD (8) Nagao A (9) Hayoun D (10) Murayama A (11) Sakaguchi Y (12) Poulis P (13) Khatib A (14) Erlanger Avigdor B (15) Gordon S (16) Cohen Shvefel S (17) Zemanek MJ (18) Nielsen MM (19) Boura-Halfon S (20) Sagie S (21) Gumpert N (22) Yang W (23) Alexeev D (24) Kyriakidou P (25) Yao W (26) Zerbib M (27) Greenberg P (28) Benedek G (29) Litchfield K (30) Petrovich-Kopitman E (31) Nagler A (32) Oren R (33) Ben-Dor S (34) Levin Y (35) Pilpel Y (36) Rodnina M (37) Cox J (38) Merbl Y (39) Satpathy AT (40) Carmi Y (41) Erhard F (42) Suzuki T (43) Buskirk AR (44) Olweus J (45) Ruppin E (46) Schlosser A (47) Samuels Y

Cancer cell - Open Access

Investigating the role of translation dysregulation in antitumor immunity, Weller, Bartok, and McGinnis et al. evaluated the effects of TYW2 – a tRNA transferase that supports reading frame maintenance in ribosomes – and found that loss of TYW2 leads to the expression of aberrant peptides, which are presented by MHC and can be recognized by CD8⁺ T cells, enhancing tumor infiltration and antitumor immune responses. Further, loss of TYW2 enhanced CD8⁺ T cell exhaustion and sensitivity to checkpoint blockade. TYW2 expression leve ls in a population of patients with melanoma predicted clinical responses and survival outcomes.

ABSTRACT: Aberrant peptides presented by major histocompatibility complex (MHC) molecules are targets for tumor eradication, as these peptides can be recognized as foreign by T cells. Protein synthesis in malignant cells is dysregulated, which may result in the generation and presentation of aberrant peptides that can be exploited for T cell-based therapies. To investigate the role of translational dysregulation in immunological tumor control, we disrupt translation fidelity by deleting tRNA wybutosine (yW)-synthesizing protein 2 (TYW2) in tumor cells and characterize the downstream impact on translation fidelity and immunogenicity using immunopeptidomics, genomics, and functional assays. These analyses reveal that TYW2 knockout (KO) cells generate immunogenic out-of-frame peptides. Furthermore, Tyw2 loss increases tumor immunogenicity and leads to anti-programmed cell death 1 (PD-1) checkpoint blockade sensitivity in vivo. Importantly, reduced TYW2 expression is associated with increased response to checkpoint blockade in patients. Together, we demonstrate that defects in translation fidelity drive tumor immunogenicity and may be leveraged for cancer immunotherapy.

Author Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (2) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7

Author Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (2) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (3) Department of Pathology, Stanford University, Stanford, CA 94305, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (4) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway; Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (5) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (6) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (7) Department of Systems Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel. (8) Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan. (9) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (10) Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan. (11) Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan. (12) Department of Physical Biochemistry, Max Planck Institute for Multidisciplinary Sciences, 37077 Gttingen, Germany. (13) Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. (14) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (15) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (16) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (17) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (18) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway; Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (19) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (20) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (21) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (22) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway; Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (23) Computational Systems Biochemistry Research Group, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany. (24) Computational Systems Biochemistry Research Group, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany. (25) Department of Pathology, Stanford University, Stanford, CA 94305, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (26) Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 7610001, Israel. (27) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (28) Tissue Typing and Immunogenetics Unit, Hadassah Hebrew University Hospital, Jerusalem 9112102, Israel. (29) CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK; Tumour Immunogenomics and Immunosurveillance Laboratory, University College London Cancer Institute, London WC1E 6DD, UK. (30) Department of Life Science Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel. (31) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (32) Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 7610001, Israel. (33) Bioinformatics Unit, Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel. (34) de Botton Institute for Protein Profiling, the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 7610001, Israel. (35) Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel. (36) Department of Physical Biochemistry, Max Planck Institute for Multidisciplinary Sciences, 37077 Gttingen, Germany. (37) Computational Systems Biochemistry Research Group, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany. (38) Department of Systems Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel. (39) Department of Pathology, Stanford University, Stanford, CA 94305, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (40) Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. (41) Faculty for Informatics and Data Science, University of Regensburg, 93040 Regensburg, Germany. (42) Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan. (43) Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. (44) Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway; Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (45) Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (46) Rudolf Virchow Center, Center for Integrative and Translational Bioimaging, Julius-Maximilians-University Wrzburg, 97080 Wrzburg, Germany. (47) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: yardena.samuels@weizmann.ac.il.

Citation: Cancer Cell 2025 Mar 21 Epub03/21/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40154482

Tags:

CAR T cells based on fully human T cell receptor-mimetic antibodies exhibit potent antitumor activity in vivo Spotlight

(1) Salzler R (2) DiLillo DJ (3) Saotome K (4) Bray K (5) Mohrs K (6) Hwang H (7) Cygan KJ (8) Shah D (9) Rye-Weller A (10) Kundu K (11) Badithe A (12) Zhang X (13) Garnova E (14) Torres M (15) Dhanik A (16) Babb R (17) Delfino FJ (18) Thwaites C (19) Dudgeon D (20) Moore MJ (21) Meagher TC (22) Decker CE (23) Owczarek T (24) Gleason JA (25) Yang X (26) Suh D (27) Lee WY (28) Welsh R (29) MacDonald D (30) Hansen J (31) Guo C (32) Kirshner JR (33) Thurston G (34) Huang T (35) Franklin MC (36) Yancopoulos GD (37) Lin JC (38) Macdonald LE (39) Murphy AJ (40) Chen G (41) Olsen O (42) Olson WC

Science translational medicine

Using mass spectrometry, bioinformatics, and cryo-EM, Salzler and DiLillo et al. built a pipeline to identify and engineer high-affinity TCR-mimetic (TCRm) antibodies that recognize multiple peptide–cognate HLA (pHLA) complexes (MAGE-A4, KRAS G12D, and others) with high specificity, allowing CAR T cells to target intracellular tumor antigens. TCRm antibodies reformatted as CARs in human T cells targeting MAGE-A4, NY-ESO, and TYR exhibited potent tumor control in vivo, with robust cytokine production and cytotoxicity. The CD28 costimulatory signaling domain was more potent than 4-1BB across different antigens.

Contributed by Shishir Pant

(1) Salzler R (2) DiLillo DJ (3) Saotome K (4) Bray K (5) Mohrs K (6) Hwang H (7) Cygan KJ (8) Shah D (9) Rye-Weller A (10) Kundu K (11) Badithe A (12) Zhang X (13) Garnova E (14) Torres M (15) Dhanik A (16) Babb R (17) Delfino FJ (18) Thwaites C (19) Dudgeon D (20) Moore MJ (21) Meagher TC (22) Decker CE (23) Owczarek T (24) Gleason JA (25) Yang X (26) Suh D (27) Lee WY (28) Welsh R (29) MacDonald D (30) Hansen J (31) Guo C (32) Kirshner JR (33) Thurston G (34) Huang T (35) Franklin MC (36) Yancopoulos GD (37) Lin JC (38) Macdonald LE (39) Murphy AJ (40) Chen G (41) Olsen O (42) Olson WC

Science translational medicine

Using mass spectrometry, bioinformatics, and cryo-EM, Salzler and DiLillo et al. built a pipeline to identify and engineer high-affinity TCR-mimetic (TCRm) antibodies that recognize multiple peptide–cognate HLA (pHLA) complexes (MAGE-A4, KRAS G12D, and others) with high specificity, allowing CAR T cells to target intracellular tumor antigens. TCRm antibodies reformatted as CARs in human T cells targeting MAGE-A4, NY-ESO, and TYR exhibited potent tumor control in vivo, with robust cytokine production and cytotoxicity. The CD28 costimulatory signaling domain was more potent than 4-1BB across different antigens.

Contributed by Shishir Pant

ABSTRACT: Monoclonal antibody therapies have transformed the lives of patients across a diverse range of diseases. However, antibodies can usually only access extracellular proteins, including the extracellular portions of membrane proteins that are expressed on the cell surface. In contrast, T cell receptors (TCRs) survey the entire cellular proteome when processed and presented as peptides in association with human leukocyte antigen (pHLA complexes). Antibodies that mimic TCRs by recognizing pHLA complexes have the potential to extend the reach of antibodies to this larger pool of targets and provide increased binding affinity and specificity. A major challenge in developing TCR mimetic (TCRm) antibodies is the limited sequence differences between the target pHLA complex relative to the large global repertoire of pHLA complexes. Here, we provide a comprehensive strategy for generating fully human TCRm antibodies across multiple HLA alleles, beginning with pHLA target discovery and validation and culminating in the engineering of TCRm-based chimeric antigen receptor T cells with potent antitumor activity. By incorporating mass spectrometry, bioinformatic predictions, HLA-humanized mice, antibody screening, and cryo-electron microscopy, we have established a pipeline to identify additional pHLA complex-specific antibodies with therapeutic potential.

Author Info: (1) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (2) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (3) Rege

Author Info: (1) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (2) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (3) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (4) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (5) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (6) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (7) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (8) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (9) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (10) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (11) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (12) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (13) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (14) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (15) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (16) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (17) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (18) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (19) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (20) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (21) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (22) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (23) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (24) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (25) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (26) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (27) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (28) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (29) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (30) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (31) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (32) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (33) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (34) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (35) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (36) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (37) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (38) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (39) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (40) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (41) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. (42) Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.

Citation: Sci Transl Med 2025 Mar 26 17:eado9371 Epub03/26/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40138458

Tags:

Spatial immune scoring system predicts hepatocellular carcinoma recurrence Spotlight

(1) Jia G (2) He P (3) Dai T (4) Goh D (5) Wang J (6) Sun M (7) Wee F (8) Li F (9) Lim JCT (10) Hao S (11) Liu Y (12) Lim TKH (13) Ngo NT (14) Tao Q (15) Wang W (16) Umar A (17) Nashan B (18) Zhang Y (19) Ding C (20) Yeong J (21) Liu L (22) Sun C

Nature

Jia et al. developed the tumor immune microenvironment spatial (TIMES) score, integrating the spatial expression of five biomarkers (SPON2, ZFP36L2, ZFP36, VIM, HLA-DRB1) to predict HCC recurrence risk. They identified NK cell distribution patterns in 61 patients, and validated the TIMES score as superior to standard risk stratification tools in 231 patients across five cohorts. In non-recurrent cases, SPON2⁺ NK cells localized to the tumor center and showed higher activation and cytotoxic marker expression. Knockout of SPON2 in NK cells reduced immune infiltration and IFNγ production in NK and CD8⁺ T cells, and accelerated HCC tumor growth.

Contributed by Shishir Pant

(1) Jia G (2) He P (3) Dai T (4) Goh D (5) Wang J (6) Sun M (7) Wee F (8) Li F (9) Lim JCT (10) Hao S (11) Liu Y (12) Lim TKH (13) Ngo NT (14) Tao Q (15) Wang W (16) Umar A (17) Nashan B (18) Zhang Y (19) Ding C (20) Yeong J (21) Liu L (22) Sun C

Nature

Jia et al. developed the tumor immune microenvironment spatial (TIMES) score, integrating the spatial expression of five biomarkers (SPON2, ZFP36L2, ZFP36, VIM, HLA-DRB1) to predict HCC recurrence risk. They identified NK cell distribution patterns in 61 patients, and validated the TIMES score as superior to standard risk stratification tools in 231 patients across five cohorts. In non-recurrent cases, SPON2⁺ NK cells localized to the tumor center and showed higher activation and cytotoxic marker expression. Knockout of SPON2 in NK cells reduced immune infiltration and IFNγ production in NK and CD8⁺ T cells, and accelerated HCC tumor growth.

Contributed by Shishir Pant

ABSTRACT: Given the high recurrence rates of hepatocellular carcinoma (HCC) post-resection(1-3), improved early identification of patients at high risk for post-resection recurrence would help to improve patient outcomes and prioritize healthcare resources(4-6). Here we observed a spatial and HCC recurrence-associated distribution of natural killer (NK) cells in the invasive front and tumour centre from 61 patients. Using extreme gradient boosting and inverse-variance weighting, we developed the tumour immune microenvironment spatial (TIMES) score based on the spatial expression patterns of five biomarkers (SPON2, ZFP36L2, ZFP36, VIM and HLA-DRB1) to predict HCC recurrence risk. The TIMES score (hazard ratio_=_88.2, P_<_0.001) outperformed current standard tools for patient risk stratification including the TNM and BCLC systems. We validated the model in 231 patients from five multicentred cohorts, achieving a real-world accuracy of 82.2% and specificity of 85.7%. The predictive power of these biomarkers emerged through the integration of their spatial distributions, rather than individual marker expression levels alone. In vivo models, including NK cell-specific Spon2-knockout mice, revealed that SPON2 enhances IFN_ secretion and NK cell infiltration at the invasive front. Our study introduces TIMES, a publicly accessible tool for predicting HCC recurrence risk, offering insights into its potential to inform treatment decisions for early-stage HCC.

Author Info: (1) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The

Author Info: (1) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China. (2) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (3) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (4) Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore. (5) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (6) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (7) Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore. (8) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (9) Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore. (10) Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China. (11) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (12) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Duke-NUS Medical School, Singapore, Singapore. (13) Duke-NUS Medical School, Singapore, Singapore. (14) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (15) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (16) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (17) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. (18) Hunan Cancer Hospital, The Affiliated Cancer Hospital of Central South University, Changsha, China. (19) State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Fudan University, Shanghai, China. (20) Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore. yeongps@imcb.a-star.edu.sg. Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore. yeongps@imcb.a-star.edu.sg. Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Singapore, Singapore. yeongps@imcb.a-star.edu.sg. Cancer Science Institute, National University of Singapore, Singapore, Singapore. yeongps@imcb.a-star.edu.sg. (21) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. liulx@ustc.edu.cn. (22) Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China. charless@ustc.edu.cn. Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. charless@ustc.edu.cn.

Citation: Nature 2025 Mar 12 Epub03/12/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40074893

Tags:

A B7H3-targeting antibody-drug conjugate in advanced solid tumors: a phase 1/1b trial Spotlight

(1) Ma Y (2) Yang Y (3) Huang Y (4) Fang W (5) Xue J (6) Meng X (7) Fan Y (8) Fu S (9) Wu L (10) Zheng Y (11) Liu J (12) Liu Z (13) Zhuang W (14) Rosen S (15) Qu S (16) Li B (17) Li M (18) Zhao Y (19) Yang S (20) Ji Y (21) Sommerhalder D (22) Luo S (23) Yang K (24) Li J (25) Lv D (26) Zhang P (27) Zhao Y (28) Hong S (29) Zhang Y (30) Zhao S (31) Chin S (32) Zhang X (33) Lian W (34) Cai J (35) Xue T (36) Zhang L (37) Zhao H

Nature medicine

In a phase 1/1b trial, Ma et al. evaluated YL201, a B7H3-targeting antibody–drug conjugate (ADC), in 312 heavily pretreated patients with advanced solid tumors. YL201 releases its conjugated topoisomerase 1 inhibitor after cleavage in both the TME and the intracellular lysosome. The objective response rate was 40.8%, and the disease control rate was 83.6%, with a median PFS of 5.9 months and a median response duration of 6.3 months. Grade 3 or higher AEs occurred in 54.5% of patients, as seen for other B7H3 ADCs. YL201 activity was not dependent on B7H3 expression levels or soluble B7H3 concentrations. Phase 3 trials of YL201 are underway.

Contributed by Ute Burkhardt

(1) Ma Y (2) Yang Y (3) Huang Y (4) Fang W (5) Xue J (6) Meng X (7) Fan Y (8) Fu S (9) Wu L (10) Zheng Y (11) Liu J (12) Liu Z (13) Zhuang W (14) Rosen S (15) Qu S (16) Li B (17) Li M (18) Zhao Y (19) Yang S (20) Ji Y (21) Sommerhalder D (22) Luo S (23) Yang K (24) Li J (25) Lv D (26) Zhang P (27) Zhao Y (28) Hong S (29) Zhang Y (30) Zhao S (31) Chin S (32) Zhang X (33) Lian W (34) Cai J (35) Xue T (36) Zhang L (37) Zhao H

Nature medicine

In a phase 1/1b trial, Ma et al. evaluated YL201, a B7H3-targeting antibody–drug conjugate (ADC), in 312 heavily pretreated patients with advanced solid tumors. YL201 releases its conjugated topoisomerase 1 inhibitor after cleavage in both the TME and the intracellular lysosome. The objective response rate was 40.8%, and the disease control rate was 83.6%, with a median PFS of 5.9 months and a median response duration of 6.3 months. Grade 3 or higher AEs occurred in 54.5% of patients, as seen for other B7H3 ADCs. YL201 activity was not dependent on B7H3 expression levels or soluble B7H3 concentrations. Phase 3 trials of YL201 are underway.

Contributed by Ute Burkhardt

ABSTRACT: Antibody-drug conjugates (ADCs) have emerged as a transformative modality in the treatment of solid tumors. YL201, a novel B7H3-targeting ADC, leverages a tumor microenvironment activable linker-payload platform, coupled with a novel topoisomerase 1 inhibitor via a protease-cleavable linker. Here we report the findings from a large-scale, global, multicenter, phase 1 trial evaluating the safety, pharmacokinetics and preliminary efficacy of YL201 in patients with advanced solid tumors refractory to standard therapies. The trial included a dose-escalation part (phase 1) and a dose-expansion part (phase 1b). A total of 312 patients were enrolled across multiple tumor types, including extensive-stage small cell lung cancer (ES-SCLC), nasopharyngeal carcinoma (NPC), non-small cell lung cancer, esophageal squamous cell carcinoma and other solid tumors. The maximum tolerated dose was determined to be 2.8_mg_kg(-1), and the recommended expansion dose was selected as 2.0_mg_kg(-1) and 2.4_mg_kg(-1) every 3_weeks. The most common grade 3 or higher treatment-related adverse events included neutropenia (31.7%), leukopenia (29.5%) and anemia (25.0%). Only 4 cases of interstitial lung disease (1.3%) and 1 case of infusion reactions (0.3%) were observed. Encouraging anti-tumor activity was observed, particularly in patients with ES-SCLC (objective response rate (ORR), 63.9%), NPC (ORR, 48.6%), lung adenocarcinoma (ORR, 28.6%) and lymphoepithelioma-like carcinoma (ORR, 54.2%). No significant correlation between B7H3 membrane expression and the ORR was found. YL201 demonstrated an acceptable safety profile and a promising efficacy in heavily pretreated patients with advanced solid tumors, particularly in those with ES-SCLC, NPC or lymphoepithelioma-like carcinoma. Phase 3 clinical trials for patients with SCLC and NPC have already been initiated. ClinicalTrials.gov identifiers: NCT05434234 and NCT06057922 .

Author Info: (1) Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Dia

Author Info: (1) Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (2) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (3) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (4) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (5) Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (6) Department of Chest Radiotherapy IV, Shandong Cancer Hospital and Institute, Jinan, China. (7) Department of Chest Medicine, Zhejiang Cancer Hospital, Hangzhou, China. (8) The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Internal Thoracic, Hunan Cancer Hospital, Changsha, China. (10) Department of Medical Oncology/Clinical Pharmacy Research Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (11) Department of Medical Oncology/Clinical Pharmacy Research Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (12) Department of Thoracic Tumor Radiotherapy I, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (13) Department of Thoracic Oncology, Fujian Cancer Hospital, Fuzhou, China. (14) Hematology Oncology Associates of the Treasure Coast, Port Saint Lucie, FL, USA. (15) Department of Radiotherapy, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, China. (16) Department of Medical Oncology, The Second Affiliated Hospital of Guilin Medical University, Guilin, China. (17) Department of Oncology II, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. (18) Department of Respiratory Medicine I, Henan Cancer Hospital, Zhengzhou, China. (19) Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China. (20) Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China. (21) NEXT Oncology, San Antonio, TX, USA. (22) Phase I Clinical Trial Center, Henan Cancer Hospital, Zhengzhou, China. (23) Department of Head and Neck Oncology, Union Hospital Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (24) Department of Head and Neck Radiotherapy II, Jiangxi Cancer Hospital (Jiangxi Second People's Hospital), Nanchang, China. (25) Department of Respiratory Medicine, Taizhou Hospital of Zhejiang Province, Taizhou, China. (26) Department of Radiotherapy, Sichuan Cancer Hospital, Chengdu, China. (27) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (28) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (29) Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (30) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (31) MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China. (32) MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China. (33) MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China. (34) MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China. (35) MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China. tony@medilinkthera.com. (36) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. zhangli@sysucc.org.cn. (37) Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. zhaohy@sysucc.org.cn.

Citation: Nat Med 2025 Mar 13 Epub03/13/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40082695

Tags:

Redirecting immune signaling with cytokine adaptors Spotlight

(1) Abhiraman GC (2) Householder KD (3) Rodriguez GE (4) Glassman CR (5) Saxton RA (6) Breuer CB (7) Wilson SC (8) Su L (9) Yen M (10) Hsu C (11) Pillarisetty VG (12) Reticker-Flynn NE (13) Garcia KC

Nature communications - Open Access | Free PMC Article

To reroute a cytokine’s signaling, Abhiraman et al. generated soluble adaptors comprising units that bind to two sites on a cytokine linked to units that bind to and compel dimerization/activation of a different cytokine’s receptor. Adaptors linking an scFv specific for dimeric TGFβ or an scFv to IL-10 and IL10R-domain to VHHs specific for IL-2Rβ or γc chains were shown to lack intrinsic signaling activity, but in the presence of immunosuppressive TGFβ or IL-10, respectively, agonized IL-2R mediated proinflammatory effector functions of human T cells in vitro. Structurally analogous adaptors converted proinflammatory IL-23 and IL-17 into immunosuppressive IL-10R agonists.

Contributed by Paula Hochman

(1) Abhiraman GC (2) Householder KD (3) Rodriguez GE (4) Glassman CR (5) Saxton RA (6) Breuer CB (7) Wilson SC (8) Su L (9) Yen M (10) Hsu C (11) Pillarisetty VG (12) Reticker-Flynn NE (13) Garcia KC

Nature communications - Open Access | Free PMC Article

To reroute a cytokine’s signaling, Abhiraman et al. generated soluble adaptors comprising units that bind to two sites on a cytokine linked to units that bind to and compel dimerization/activation of a different cytokine’s receptor. Adaptors linking an scFv specific for dimeric TGFβ or an scFv to IL-10 and IL10R-domain to VHHs specific for IL-2Rβ or γc chains were shown to lack intrinsic signaling activity, but in the presence of immunosuppressive TGFβ or IL-10, respectively, agonized IL-2R mediated proinflammatory effector functions of human T cells in vitro. Structurally analogous adaptors converted proinflammatory IL-23 and IL-17 into immunosuppressive IL-10R agonists.

Contributed by Paula Hochman

ABSTRACT: Cytokines are signaling molecules that coordinate complex immune processes and are frequently dysregulated in disease. While cytokine blockade has become a common therapeutic modality, cytokine agonism has had limited utility due to the widespread expression of cytokine receptors with pleiotropic effects. To overcome this limitation, we devise an approach to engineer molecular switches, termed cytokine adaptors, that transform one cytokine signal into an alternative signal with a different functional output. Endogenous cytokines act to nucleate the adaptors, converting the cytokine-adaptor complex into a surrogate agonist for a different cytokine pathway. In this way, cytokine adaptors, which have no intrinsic agonist activity, can function as conditional, context-dependent agonists. We develop cytokine adaptors that convert IL-10 or TGF-_ into IL-2 receptor agonists to reverse T cell suppression. We also convert the pro-inflammatory cytokines IL-23 or IL-17 into immunosuppressive IL-10 receptor agonists. Thus, we show that cytokine adaptors can convert immunosuppressive cytokines into immunostimulatory cytokines, or vice versa. Unlike other methods of immune conversion that require cell engineering, cytokine adaptors are soluble molecules that leverage endogenous cues from the microenvironment to drive context-specific signaling.

Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. Program in Immunology, Stanford University

Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. Program in Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA. (2) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. Program in Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA. (3) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. Program in Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA. (4) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. (5) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. (6) Program in Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA. Department of Otolaryngology - Head & Neck Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA. (7) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. (8) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. (9) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. (10) Department of Surgery, University of Washington School of Medicine, Seattle, WA, 98112, USA. (11) Department of Surgery, University of Washington School of Medicine, Seattle, WA, 98112, USA. (12) Department of Otolaryngology - Head & Neck Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA. (13) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. kcgarcia@stanford.edu. Howard Hughes Medical Institute, Stanford University, Stanford, CA, 94305, USA. kcgarcia@stanford.edu.

Citation: Nat Commun 2025 Mar 11 16:2432 Epub03/11/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40069219

Tags:

CD4+ anti-TGF-β CAR T cells and CD8+ conventional CAR T cells exhibit synergistic antitumor effects
Spotlight

(1) Zheng D (2) Qin L (3) Lv J (4) Che M (5) He B (6) Zheng Y (7) Lin S (8) Qi Y (9) Li M (10) Tang Z (11) Wang BC (12) Wu YL (13) Weinkove R (14) Carson G (15) Yao Y (16) Wong N (17) Lau J (18) Thiery JP (19) Qin D (20) Pan B (21) Xu K (22) Zhang Z (23) Li P

Cell reports. Medicine - Open Access

Zheng and Qin et al. engineered third-generation CAR T cells targeting TGFβ, and showed that CD4⁺, but not CD8⁺ anti-TGFβ CAR T cells (T28zT2 T cells) suppressed tumor growth. Tumor-infiltrating CD4⁺ T28zT2 T cells were enriched in a memory-like (TCF-1⁺IL7R⁺) T cell phenotype, maintained mitochondrial function, did not cause in vivo toxicity, and improved untransduced CD8⁺ T cell expansion and persistence in vivo. The combination of CD4⁺ T28zT2 T cells with CD8⁺ anti-glypican-3 (GPC3) or anti-mesothelin (MSLN) CAR T cells showed improved antitumor effects compared with conventional CD3⁺ CAR T cells.

Contributed by Shishir Pant

(1) Zheng D (2) Qin L (3) Lv J (4) Che M (5) He B (6) Zheng Y (7) Lin S (8) Qi Y (9) Li M (10) Tang Z (11) Wang BC (12) Wu YL (13) Weinkove R (14) Carson G (15) Yao Y (16) Wong N (17) Lau J (18) Thiery JP (19) Qin D (20) Pan B (21) Xu K (22) Zhang Z (23) Li P

Cell reports. Medicine - Open Access

Zheng and Qin et al. engineered third-generation CAR T cells targeting TGFβ, and showed that CD4⁺, but not CD8⁺ anti-TGFβ CAR T cells (T28zT2 T cells) suppressed tumor growth. Tumor-infiltrating CD4⁺ T28zT2 T cells were enriched in a memory-like (TCF-1⁺IL7R⁺) T cell phenotype, maintained mitochondrial function, did not cause in vivo toxicity, and improved untransduced CD8⁺ T cell expansion and persistence in vivo. The combination of CD4⁺ T28zT2 T cells with CD8⁺ anti-glypican-3 (GPC3) or anti-mesothelin (MSLN) CAR T cells showed improved antitumor effects compared with conventional CD3⁺ CAR T cells.

Contributed by Shishir Pant

ABSTRACT: Transforming growth factor (TGF)-β1 restricts the expansion, survival, and function of CD4+ T cells. Here, we demonstrate that CD4+ but not CD8+ anti-TGF-β CAR T cells (T28zT2 T cells) can suppress tumor growth partly through secreting Granzyme B and interferon (IFN)-γ. TGF-β1-treated CD4+ T28zT2 T cells persist well in peripheral blood and tumors, maintain their mitochondrial form and function, and do not cause in vivo toxicity. They also improve the expansion and persistence of untransduced CD8+ T cells in vivo. Tumor-infiltrating CD4+ T28zT2 T cells are enriched with TCF-1+IL7R+ memory-like T cells, express NKG2D, and downregulate T cell exhaustion markers, including PD-1 and LAG3. Importantly, a combination of CD4+ T28zT2 T cells and CD8+ anti-glypican-3 (GPC3) or anti-mesothelin (MSLN) CAR T cells exhibits augmented antitumor effects in xenografts. These findings suggest that rewiring TGF-β signaling with T28zT2 in CD4+ T cells is a promising strategy for eradicating solid tumors.

Author Info: (1) China-New Zealand Joint Laboratory on Biomedicine and Health, National Key Laboratory of Immune Response and Immunotherapy, Guangdong Provincial Key Laboratory of Stem Cell and

Author Info: (1) China-New Zealand Joint Laboratory on Biomedicine and Health, National Key Laboratory of Immune Response and Immunotherapy, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China. (2) China-New Zealand Joint Laboratory on Biomedicine and Health, National Key Laboratory of Immune Response and Immunotherapy, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. (3) China-New Zealand Joint Laboratory on Biomedicine and Health, National Key Laboratory of Immune Response and Immunotherapy, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. (4) China-New Zealand Joint Laboratory on Biomedicine and Health, National Key Laboratory of Immune Response and Immunotherapy, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. (5) Department of Radiology, Translational Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumor Microenvironment, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. (6) China-New Zealand Joint Laboratory on Biomedicine and Health, National Key Laboratory of Immune Response and Immunotherapy, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. (7) China-New Zealand Joint Laboratory on Biomedicine and Health, National Key Laboratory of Immune Response and Immunotherapy, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. (8) Blood Disease Institution, Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China. (9) Department of Surgery of the Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China. (10) Guangdong Zhaotai Cell Biology Technology Ltd., Foshan, China. (11) Guangdong Lung Cancer Institute, Guangdong General Hospital (GGH) & Guangdong Academy of Medical Sciences, Guangzhou, China. (12) Guangdong Lung Cancer Institute, Guangdong General Hospital (GGH) & Guangdong Academy of Medical Sciences, Guangzhou, China. (13) Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand. (14) Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand. (15) China-New Zealand Joint Laboratory on Biomedicine and Health, National Key Laboratory of Immune Response and Immunotherapy, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. (16) Department of Surgery of the Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China. (17) Department of Surgery of the Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China. (18) Guangzhou Laboratory, Guangzhou, China. (19) The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. (20) Blood Disease Institution, Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China. (21) Blood Disease Institution, Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China. (22) Department of Radiology, Translational Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumor Microenvironment, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. (23) China-New Zealand Joint Laboratory on Biomedicine and Health, National Key Laboratory of Immune Response and Immunotherapy, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China. Electronic address: li_peng@gibh.ac.cn.

Citation: Cell Rep Med 2025 Mar 18 6:102020 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40107245

Tags:

PD-1(IR2) promotes tumor evasion via deregulating CD8+ T cell function
Spotlight

(1) Zang H (2) Liu T (3) Wang X (4) Cheng S (5) Zhu X (6) Huang C (7) Duan L (8) Zhao X (9) Guo F (10) Wang X (11) Zhang C (12) Yang F (13) Gu Y (14) Hu H (15) Gao S

Journal for immunotherapy of cancer - Open Access | Free PMC Article

Zang et al. found that due to alternative splicing events in tumors, an isoform of PDCD1 retaining the exon 2 PD-L1 binding domain and the second intron (PD-1^IR2) was expressed in a variety of human leukemia cell lines, clinical tumor biopsies, and TILs. PD-1^IR2 expression was induced upon T cell activation, and was regulated by the RNA-binding protein hnRNPLL. Like PD-1, PD-1^IR2 inhibited CD8⁺ T cell proliferation, functionality, and tumor cell killing, allowing for increased tumor immune evasion. This suggested that PD-1^IR2 acts as an immune checkpoint. Further, PD-1^IR2 knock-in mice showed resistance to anti-PD-L1 compared with wild-type mice.

Contributed by Lauren Hitchings

(1) Zang H (2) Liu T (3) Wang X (4) Cheng S (5) Zhu X (6) Huang C (7) Duan L (8) Zhao X (9) Guo F (10) Wang X (11) Zhang C (12) Yang F (13) Gu Y (14) Hu H (15) Gao S

Journal for immunotherapy of cancer - Open Access | Free PMC Article

Zang et al. found that due to alternative splicing events in tumors, an isoform of PDCD1 retaining the exon 2 PD-L1 binding domain and the second intron (PD-1^IR2) was expressed in a variety of human leukemia cell lines, clinical tumor biopsies, and TILs. PD-1^IR2 expression was induced upon T cell activation, and was regulated by the RNA-binding protein hnRNPLL. Like PD-1, PD-1^IR2 inhibited CD8⁺ T cell proliferation, functionality, and tumor cell killing, allowing for increased tumor immune evasion. This suggested that PD-1^IR2 acts as an immune checkpoint. Further, PD-1^IR2 knock-in mice showed resistance to anti-PD-L1 compared with wild-type mice.

Contributed by Lauren Hitchings

BACKGROUND: The programmed cell death 1 (PD-1) is an immune checkpoint that mediates immune evasion of tumors. Alternative splicing (AS) such as intron retention (IR) plays a crucial role in the immune-related gene processing and its function. However, it is not clear whether PDCD1 encoding PD-1 exists as an IR splicing isoform and what underlying function of such isoform plays in tumor evasion. METHODS: An AS isoform of human PDCD1, characterized by the second IR and named PD-1(IR2), was identified by reverse transcription-PCR (RT-PCR) and Sanger sequencing. The expression profile of PD1(IR2) was assessed by quantitative RT-PCR and flow cytometry, while its function was evaluated through immune cell proliferation, cytokine interleukin 2 secretion, and tumor cell killing assays. PDCD1(IR2) (CKI) mice which specifically conditional knock-in PDCD1(IR2) in T cells and humanized peripheral blood mononuclear cells (PBMC)-NOG (NOD.Cg-PrkdcscidIL2rgtm1Sug/JicCrl) mice were utilized to further confirm the physiological function of PD-1(IR2) in vivo. RESULTS: PD-1(IR2) is expressed in a variety of human leukemia cell lines and tumor-infiltrating lymphocytes. PD-1(IR2) expression is induced on T cell activation and regulated by the RNA-binding protein hnRNPLL. PD-1(IR2) negatively regulates the immune function of CD8(+) T cells, indicated by inhibiting T cell proliferation, cytokine production, and tumor cell killing in vitro. PD-1(IR2+) CD8(+) T cells show impaired antitumor function, which consequently promote tumor evasion in a conditional knock-in mouse model and a PBMC-engrafted humanized NOG mouse model. PD-1(IR2) mice exhibit resistance to anti-PD-L1 therapy compared with wild-type mice. CONCLUSIONS: PD-1(IR2) is a potential immune checkpoint that may mediate potential resistance to immune checkpoint therapy.

Author Info: (1) Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China. Shanxi Academy of Advanced Research and Innovation, Taiyuan, Shanxi, China. (2) Sc

Author Info: (1) Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China. Shanxi Academy of Advanced Research and Innovation, Taiyuan, Shanxi, China. (2) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. Medical College, Guizhou University, Guiyang, Guizhou, China. (3) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. (4) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. Medical School of Nanjing University, Nanjing, Jiangsu, China. (5) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. Medical College, Guizhou University, Guiyang, Guizhou, China. (6) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. Medical College, Guizhou University, Guiyang, Guizhou, China. (7) Shanxi Academy of Advanced Research and Innovation, Taiyuan, Shanxi, China. School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. (8) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. (9) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, Shanxi, China. (10) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. (11) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. Department of oncology, The Key Laboratory of Advanced Interdisciplinary Studies, First Affiliated Hospital of Guangzhou Medical University State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong, China. (12) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. (13) The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China gaos@sibet.ac.cn hongbohu@scu.edu.cn guym_81@126.com. School of Medicine, Southeast University, Nanjing, Jiangsu, China. (14) Center for Immunology and Hematology, Department of Biotherapy and Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China gaos@sibet.ac.cn hongbohu@scu.edu.cn guym_81@126.com. (15) Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China gaos@sibet.ac.cn hongbohu@scu.edu.cn guym_81@126.com. School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China.

Citation: J Immunother Cancer 2025 Mar 6 13: Epub03/06/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40050045

New soluble CSF-1R-dimeric mutein with enhanced trapping of both CSF-1 and IL-34 reduces suppressive tumor-associated macrophages in pleural mesothelioma Spotlight

Tags:

Embryonic reprogramming of the tumor vasculature reveals targets for cancer therapy Spotlight

Tags:

A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells Spotlight

Tags:

Translation dysregulation in cancer as a source for targetable antigens Featured

Tags:

CAR T cells based on fully human T cell receptor-mimetic antibodies exhibit potent antitumor activity in vivo Spotlight

Tags:

Spatial immune scoring system predicts hepatocellular carcinoma recurrence Spotlight

Tags:

A B7H3-targeting antibody-drug conjugate in advanced solid tumors: a phase 1/1b trial Spotlight

Tags:

Redirecting immune signaling with cytokine adaptors Spotlight

Tags:

CD4+ anti-TGF-β CAR T cells and CD8+ conventional CAR T cells exhibit synergistic antitumor effects Spotlight

Tags:

PD-1(IR2) promotes tumor evasion via deregulating CD8+ T cell function Spotlight

Tags:

Subscribe to our mailing list

GDPR Marketing Permissions

Small change for you. Big change for us!

This Thanksgiving season, show your support for cancer research by donating your change.

CD4+ anti-TGF-β CAR T cells and CD8+ conventional CAR T cells exhibit synergistic antitumor effects
Spotlight

PD-1(IR2) promotes tumor evasion via deregulating CD8+ T cell function
Spotlight