Journal Articles

Local delivery of IL-15 and anti-PD-L1 nanobody by in vitro transcript circILNb elicits superior antitumor immunity in cold tumors

Spotlight 

Dun Niu 1, Xiaozhuang Ma 1, Junshi Zhu 1, Liangbo Sun 1, Shaotong Zhang 1, Yaran Wu 1, Meihua Shan 1, Xufang Dai 2, Yaling Liao 1, Dong Liu 1, Lu Lu 1, Mingzhen Yang 3, Quanming Zou 4, Jiqin Lian 5

Cell Reports Medicine

Niu, Ma, Zhu, and Sun et al. constructed circILNb, a circular RNA encoding a blocking anti-PD-L1 Nb and bioactive IL-15/IL-15Rα, which after purification via a novel biotin-avidin system, was delivered i.t. in LNPs. CircILNb enabled sustained robust in situ protein expression, tumor inhibition (dependent on activation of pre-existing CD8+ T and NK TILs and on IFNγ), and extended survival in four models of advanced “cold” tumors in mice, without systemic toxicity, and better than protein-based therapeutics. CircILNb-loaded DCs migrated to tdLNs to promote antigen-specific CD8+ T cell-mediated regression of distal tumors and metastases.

Contributed by Paula Hochman

Dun Niu 1, Xiaozhuang Ma 1, Junshi Zhu 1, Liangbo Sun 1, Shaotong Zhang 1, Yaran Wu 1, Meihua Shan 1, Xufang Dai 2, Yaling Liao 1, Dong Liu 1, Lu Lu 1, Mingzhen Yang 3, Quanming Zou 4, Jiqin Lian 5

Cell Reports Medicine

Niu, Ma, Zhu, and Sun et al. constructed circILNb, a circular RNA encoding a blocking anti-PD-L1 Nb and bioactive IL-15/IL-15Rα, which after purification via a novel biotin-avidin system, was delivered i.t. in LNPs. CircILNb enabled sustained robust in situ protein expression, tumor inhibition (dependent on activation of pre-existing CD8+ T and NK TILs and on IFNγ), and extended survival in four models of advanced “cold” tumors in mice, without systemic toxicity, and better than protein-based therapeutics. CircILNb-loaded DCs migrated to tdLNs to promote antigen-specific CD8+ T cell-mediated regression of distal tumors and metastases.

Contributed by Paula Hochman

ABSTRACT: The clinical translation of combined immunocytokine (IC) and immune checkpoint inhibitor (ICI) is constrained by relapse of advanced malignancies, systemic toxicities, and prohibitive research and synthesis costs. In this study, the circCV-B3 vector is constructed to enable scarless circular RNA (circRNA) engineering. The circILNb, engineered via the circCV-B3 vector, enables co-encoding of interleukin-15 (IL-15) and anti-PD-L1 nanobody (Nb). The circILNb is purified by biotin-avidin purification system (BAPS) and is encapsulated within lipid nanoparticles (LNPs). Intratumoral circILNb administration achieves in situ protein expression, achieving local tumor control. Furthermore, dendritic cells (DCs) load circILNb and migrate to tumor-draining lymph node (tdLN), where they prime antigen-specific CD8+ T cell activation, eliciting a robust systemic immune response. These findings highlight the potential of circCV-B3 vector and BAPS as a methodology for circRNA engineering and substantiate circILNb as non-protein-based therapeutic strategy for tumor immunotherapy.

Author Info: 1 - Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. 2 - College of Education and Science, Chongq

Author Info: 1 - Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. 2 - College of Education and Science, Chongqing Normal University, Chongqing 400047, China. 3 - Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: yangmingzhen0807@126.com. 4 - National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: qmzou2007@163.com. 5 - Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: lianjiqin@tmmu.edu.cn.

Citation: Cel Rep. Med. Oct 10, 2025

Link to PUBMED: https://pubmed.ncbi.nlm.nih.gov/41075789/

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    Decoding tumor heterogeneity- A spatially informed pan-cancer analysis of the tumor microenvironment

    Spotlight 

    Francesca Lodi (1,2) ∙ Sam Vanmassenhove (1,2) ∙ Duojiao Chen (3) ∙ Bram Boeckx (1,2) ∙ Lucas Ferreira Maciel (2,4) ∙ Frederik Peeters (2,5) ∙ Elena Donders (2,6,7) ∙ Heesoo Song (1,2) ∙ Luuk Harbers (8) ∙ Joanna Poźniak (2,4) ∙ Liselore Loverix (9,10) ∙ Yiduo Zhou (3) ∙ Michel Bila (11,12) ∙ Ayse Bassez (1,2) ∙ Sarah Cappuyns (5) ∙ Tom Venken (1,2) ∙ Siel Olbrecht (9,10) ∙ Amelie Franken (1,2) ∙ Pierre Van Mol (6,7) ∙ Rogier Schepers (1,2) ∙ Thomas van Brussel (1,2) ∙ Gino Philips (1,2) ∙ Hanne Vos (13) ∙ Machteld Keupers (14) ∙ Frederik De Smet (15,16) ∙ Sabine Tejpar (5) ∙ Oliver Bechter (11,12) ∙ Gabriele Bergers (2,17) ∙ Ann Smeets (13) ∙ Paul Clement (11,12) ∙ Els Wauters (6,7) ∙ Jeroen Dekervel (5) ∙ Toon Van Gorp (9,10) ∙ Junbin Qian (3,18) ∙ Jean-Christophe Marine (2,4) ∙ Diether Lambrechts (1,2,19) diether.lambrechts@kuleuven.be

    Cell Reports Medicine

    Using scRNAseq, Lodi et al. created a pan-cancer single-cell atlas from 160 patients across 9 cancer types, and identified 70 shared cell subtypes. Two distinct hubs with subtype abundances that positively correlated with each other were identified. The first hub consisted of differentiated B cells resembling tertiary lymphoid structures, and the second hub consisted of inflammatory macrophages, PD-L1+ immune-regulatory cells, lymphatic ECs, and PD-1+ T cells. Spatial transcriptomic confirmed that cell subtypes in each hub formed a spatially defined TME, and tumors enriched for both hubs correlated with T cell reactivity and responses to ICB.

    Contributed by Shishir Pant

    Francesca Lodi (1,2) ∙ Sam Vanmassenhove (1,2) ∙ Duojiao Chen (3) ∙ Bram Boeckx (1,2) ∙ Lucas Ferreira Maciel (2,4) ∙ Frederik Peeters (2,5) ∙ Elena Donders (2,6,7) ∙ Heesoo Song (1,2) ∙ Luuk Harbers (8) ∙ Joanna Poźniak (2,4) ∙ Liselore Loverix (9,10) ∙ Yiduo Zhou (3) ∙ Michel Bila (11,12) ∙ Ayse Bassez (1,2) ∙ Sarah Cappuyns (5) ∙ Tom Venken (1,2) ∙ Siel Olbrecht (9,10) ∙ Amelie Franken (1,2) ∙ Pierre Van Mol (6,7) ∙ Rogier Schepers (1,2) ∙ Thomas van Brussel (1,2) ∙ Gino Philips (1,2) ∙ Hanne Vos (13) ∙ Machteld Keupers (14) ∙ Frederik De Smet (15,16) ∙ Sabine Tejpar (5) ∙ Oliver Bechter (11,12) ∙ Gabriele Bergers (2,17) ∙ Ann Smeets (13) ∙ Paul Clement (11,12) ∙ Els Wauters (6,7) ∙ Jeroen Dekervel (5) ∙ Toon Van Gorp (9,10) ∙ Junbin Qian (3,18) ∙ Jean-Christophe Marine (2,4) ∙ Diether Lambrechts (1,2,19) diether.lambrechts@kuleuven.be

    Cell Reports Medicine

    Using scRNAseq, Lodi et al. created a pan-cancer single-cell atlas from 160 patients across 9 cancer types, and identified 70 shared cell subtypes. Two distinct hubs with subtype abundances that positively correlated with each other were identified. The first hub consisted of differentiated B cells resembling tertiary lymphoid structures, and the second hub consisted of inflammatory macrophages, PD-L1+ immune-regulatory cells, lymphatic ECs, and PD-1+ T cells. Spatial transcriptomic confirmed that cell subtypes in each hub formed a spatially defined TME, and tumors enriched for both hubs correlated with T cell reactivity and responses to ICB.

    Contributed by Shishir Pant

    ABSTRACT: Pan-cancer single-cell atlases explore the heterogeneity of cell types residing within the tumor microenvironment (TME). So far, atlases focused on individual cell types, failing to capture the full complexity of the TME. Here, we present a single-cell atlas that simultaneously considers heterogeneity in 5 cell types, collected from 230 treatment-naive samples across 9 cancer types. We identify 70 pan-cancer single-cell subtypes, investigate their patterns of co-occurrence and show an enrichment of specific subtypes in certain TMEs, e.g., immune-reactive versus immune-suppressive TME. We observe two TME hubs of strongly co-occurring subtypes: one hub resembling tertiary lymphoid structures (TLSs), another consisting of immune-reactive PD1+/PD-L1+ immune-regulatory T cells and B cells, dendritic cells and inflammatory macrophages. Subtypes belonging to each hub are spatially co-localized, while their abundance associates with early and long-term checkpoint immunotherapy response. We publicly share our atlas using a Shiny app, allowing others to explore TME heterogeneity in different biological contexts.

    Author Info: 1- Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium 2- VIB Center for Cancer Biology, Leuven, Belgium 3- Zhejiang Key Laboratory of P

    Author Info: 1- Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium 2- VIB Center for Cancer Biology, Leuven, Belgium 3- Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China 4- Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium 5- Digestive Oncology, Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium 6- Department of Pneumology, Division of Respiratory Oncology, University Hospitals Leuven, Leuven, Belgium 7- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium 8- Bioinformatics Expertise Center, VIB Center for Cancer Biology, Leuven, Belgium 9- Department of Obstetrics and Gynaecology, Division of Gynaecological Oncology, University Hospitals Leuven, Leuven, Belgium 10- Laboratory of Gynaecologic Oncology, Department of Oncology, KU Leuven, Leuven, Belgium 11- Department of General Medical Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium 12- Laboratory of Experimental Oncology (LEO), Department of Oncology, KU Leuven, Leuven, Belgium 13- Department of Surgical Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium 14- Department of Radiology, University Hospitals Leuven, KU Leuven, Leuven, Belgium 15- Laboratory for Precision Cancer Medicine, Translational Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium 16- Leuven Institute for Single-cell Omics (LISCO), KU Leuven, Leuven, Belgium 17- Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, KU Leuven, Leuven, Belgium 18- Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, China 19- Lead contact

    Citation: Cell Rep Med Oct 13, 2025 online

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      Antibody-gamma/delta T cell receptors targeting GPC2 regress neuroblastoma with low antigen density Spotlight 

      (1) Quan A (2) Huo M (3) Li D (4) Hutchins LE (5) Rodriguez C (6) Oh J (7) Tsao HE (8) Spetz M (9) Edmondson E (10) Ashworth D (11) Zheng R (12) Zhou J (13) Chen J (14) Liu J (15) Xiong G (16) Zhang H (17) Liu C (18) Nguyen R (19) Li N (20) Ho M

      Cell reports. Medicine

      To treat neuroblastoma expressing the oncofetal antigen GPC2, Quan and Huo et al. generated "AbTCR-T cells" expressing (1) anti-GPC2 Fab linked to TCRγδ and (2) anti-GPC2 scFv linked to a CD30 costimulatory domain. The GPC2-binding domain was humanized from the murine CT3 antibody, and retained specific GPC2 binding. Compared to CAR-T, AbTCR-T had superior cytotoxicity, tumor T cell infiltration, and in vivo efficacy against tumors with high or, in particular, low antigen expression. AbTCR-T also maintained a less exhausted and more stem-like phenotype, improving serial cytotoxicity, and augmented endogenous TCR and NFAT signaling.

      Contributed by Alex Najibi

      (1) Quan A (2) Huo M (3) Li D (4) Hutchins LE (5) Rodriguez C (6) Oh J (7) Tsao HE (8) Spetz M (9) Edmondson E (10) Ashworth D (11) Zheng R (12) Zhou J (13) Chen J (14) Liu J (15) Xiong G (16) Zhang H (17) Liu C (18) Nguyen R (19) Li N (20) Ho M

      Cell reports. Medicine

      To treat neuroblastoma expressing the oncofetal antigen GPC2, Quan and Huo et al. generated "AbTCR-T cells" expressing (1) anti-GPC2 Fab linked to TCRγδ and (2) anti-GPC2 scFv linked to a CD30 costimulatory domain. The GPC2-binding domain was humanized from the murine CT3 antibody, and retained specific GPC2 binding. Compared to CAR-T, AbTCR-T had superior cytotoxicity, tumor T cell infiltration, and in vivo efficacy against tumors with high or, in particular, low antigen expression. AbTCR-T also maintained a less exhausted and more stem-like phenotype, improving serial cytotoxicity, and augmented endogenous TCR and NFAT signaling.

      Contributed by Alex Najibi

      ABSTRACT: Chimeric antigen receptor (CAR) T cells have shown promise in hematological cancers but face challenges in solid tumors, partly due to heterogeneous antigen density. Glypican-2 (GPC2) is an oncofetal antigen highly expressed in neuroblastoma and under evaluation in phase 1 clinical trials. Here, we engineer T cells with antibody-T cell receptors (AbTCRs) targeting GPC2. We generate autologous AbTCR T cells using CT3 or humanized CT3 (hCT3) antigen-binding fragments (Fab) linked to _/_ T cell receptors (TCRs), along with a CD30 co-stimulatory domain. Both CT3 and hCT3 AbTCR T cells show superior antitumor efficacy compared to CT3 CAR T cells, with hCT3 AbTCR T cells inducing significant regression in neuroblastoma with low GPC2 antigen density. Enhanced efficacy is associated with stronger TCR signaling, expansion of stem cell-like memory T cells, and improved CD8(+) T cell infiltration. These results highlight the potential of hCT3 AbTCR T cells for neuroblastoma and indicate broad application of AbTCR T cells in solid tumors.

      Author Info: (1) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (2) Laboratory of Molecular

      Author Info: (1) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (2) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (3) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (4) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (5) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (6) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (7) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (8) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (9) Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. (10) Spatomics LLC, 246 Goose Ln, Ste 202A, Guilford, CT 06437, USA. (11) Spatomics LLC, 246 Goose Ln, Ste 202A, Guilford, CT 06437, USA. (12) Spatomics LLC, 246 Goose Ln, Ste 202A, Guilford, CT 06437, USA. (13) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (14) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (15) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (16) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (17) Eureka Therapeutics Inc., 5858 Horton Street, Suite 370, Emeryville, CA 94608, USA. (18) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (19) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. (20) Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. Electronic address: homi@mail.nih.gov.

      Citation: Cell Rep Med 2025 Sep 29 102378 Epub09/29/2025

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41027430

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      CD4+ T cells mediate MHC-deficient tumor rejection and endothelial cell reprogramming Featured  

      (1) Kim SI (2) Haerr ME (3) Al-Ghezi M (4) Chen C (5) Zhang Y (6) Phipps JL (7) Arora C (8) Gribbin KP (9) Kim G (10) Markosyan N (11) Xia Z (12) Vonderheide RH (13) Byrne KT

      Cancer immunology research

      Kim and Haerr et al. demonstrated that immunotherapy using agonistic anti-CD40 and dual immune checkpoint blockade (ICB; anti-PD-1 plus anti-CTLA-4) was effective against multiple pancreatic tumor models that were deficient in MHC-I, MHC-II, and IFNγR, regardless of whether they expressed a strong antigen (OVA). CD4+, but not CD8+ T cells or perforin, were required for antitumor efficacy, and the researchers found that CD4+ T cells likely mediated responses to immunotherapy through reprogramming of MHC-II-expressing endothelial cells and remodeling of the tumor stroma.

      (1) Kim SI (2) Haerr ME (3) Al-Ghezi M (4) Chen C (5) Zhang Y (6) Phipps JL (7) Arora C (8) Gribbin KP (9) Kim G (10) Markosyan N (11) Xia Z (12) Vonderheide RH (13) Byrne KT

      Cancer immunology research

      Kim and Haerr et al. demonstrated that immunotherapy using agonistic anti-CD40 and dual immune checkpoint blockade (ICB; anti-PD-1 plus anti-CTLA-4) was effective against multiple pancreatic tumor models that were deficient in MHC-I, MHC-II, and IFNγR, regardless of whether they expressed a strong antigen (OVA). CD4+, but not CD8+ T cells or perforin, were required for antitumor efficacy, and the researchers found that CD4+ T cells likely mediated responses to immunotherapy through reprogramming of MHC-II-expressing endothelial cells and remodeling of the tumor stroma.

      ABSTRACT: Low or absent expression of major histocompatibility complex (MHC) on tumor cells is a presumed mechanism of resistance to immunotherapy, but evidence for this has largely been indirect. Likewise, whether immunotherapy can be effective without tumor MHC expression is also poorly understood. Using genetically-engineered mouse tumor cells expressing the model neoantigen ovalbumin (OVA), we found that MHC class I-deficient tumor cells, but not MHC class I-sufficient tumor cells, grew progressively when injected subcutaneously into syngeneic C57BL/6 mice. However, combination immunotherapy using agonistic anti-CD40 and dual immune checkpoint blockade (ICB) (anti-PD1 and anti-CTLA-4) was equally effective against tumors that did not express the MHC class I H-2Kb allele, MHC class II, or IFN-_ receptor across multiple pancreatic tumor lines (regardless of OVA). Moreover, CD4+ T cells, but not CD8+ T cells or perforin, were necessary to mediate immunotherapeutic responses. We excluded a role for CD4+ T cell-instructed macrophage-mediated tumor cell death but observed reprogramming of MHC class II-expressing stromal cells within the tumor after anti-CD40/ICB treatment. These data indicate that cancer immune surveillance by T cells does not absolutely require tumor-expressed MHC class I nor CD8+ T cells but instead can facilitate a clinically relevant remodeling of endothelial cells, further underscoring tumor-extrinsic roles for CD4+ T cells as mediators of tumor rejection and durable immune memory.

      Author Info: (1) University of Pennsylvania, Philadelphia, PA, United States. (2) Oregon Health and Science University Hospital, Portland, OR, United States. (3) Oregon Health and Science Unive

      Author Info: (1) University of Pennsylvania, Philadelphia, PA, United States. (2) Oregon Health and Science University Hospital, Portland, OR, United States. (3) Oregon Health and Science University Hospital, Portland, OR, United States. (4) Oregon Health & Science University, Portland, Oregon, United States. (5) Oregon Health & Science University, United States. (6) Oregon Health & Science University, United States. (7) University of Pennsylvania, Philadelphia, PA, United States. (8) Oregon Health & Science University, Portland, Oregon, United States. (9) Oregon Health & Science University, United States. (10) University of Pennsylvania, Philadelphia, PA, United States. (11) Oregon Health & Science University, Portland, OR, United States. (12) University of Pennsylvania, Philadelphia, Pennsylvania, United States. (13) Oregon Health and Science University, Portland, OR, United States.

      Citation: Cancer Immunol Res 2025 Sep 30 Epub09/30/2025

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41025699

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      Solid tumour CAR-T cells engineered with fusion proteins targeting PD-L1 for localized IL-12 delivery Spotlight 

      (1) Murad JP (2) Christian L (3) Rosa R (4) Ren Y (5) Buckley AJ (6) Lee EHJ (7) Lopez LS (8) Park AK (9) Yang J (10) Yamaguchi Y (11) Trac C (12) Adkins LN (13) Chang WC (14) Martinez C (15) June CH (16) Forman SJ (17) Ishihara J (18) Lee JK (19) Stern LA (20) Priceman SJ

      Nature biomedical engineering

      To improve CAR T cell efficacy in solid tumors, Murad et al. armored CAR T cells to secrete bifunctional fusion proteins consisting of TGFβtrap, IL-15, or IL-12 tethered to anti-PD-L1, enabling local and targeted antitumor effects with reduced systemic toxicity. In immunologically “cold” syngeneic prostate and ovarian models, anti-PD-L1 fused to IL-12 outperformed CAR T cells alone and the other combinations in efficacy and safety, enhancing T cell trafficking into the tumor, TME modulation, and localized IFNγ production, with less systemic cytokine-associated toxicity. An active human version of anti-PD-L1–IL-12 fusion was also generated.

      Contributed by Katherine Turner

      (1) Murad JP (2) Christian L (3) Rosa R (4) Ren Y (5) Buckley AJ (6) Lee EHJ (7) Lopez LS (8) Park AK (9) Yang J (10) Yamaguchi Y (11) Trac C (12) Adkins LN (13) Chang WC (14) Martinez C (15) June CH (16) Forman SJ (17) Ishihara J (18) Lee JK (19) Stern LA (20) Priceman SJ

      Nature biomedical engineering

      To improve CAR T cell efficacy in solid tumors, Murad et al. armored CAR T cells to secrete bifunctional fusion proteins consisting of TGFβtrap, IL-15, or IL-12 tethered to anti-PD-L1, enabling local and targeted antitumor effects with reduced systemic toxicity. In immunologically “cold” syngeneic prostate and ovarian models, anti-PD-L1 fused to IL-12 outperformed CAR T cells alone and the other combinations in efficacy and safety, enhancing T cell trafficking into the tumor, TME modulation, and localized IFNγ production, with less systemic cytokine-associated toxicity. An active human version of anti-PD-L1–IL-12 fusion was also generated.

      Contributed by Katherine Turner

      ABSTRACT: Chimeric antigen receptor (CAR)-T cell efficacy in solid tumours is limited due in part to the immunosuppressive tumour microenvironment (TME). To improve antitumour responses, we hypothesized that enabling CAR-T cells to secrete bifunctional fusion proteins consisting of a cytokine modifier such as TGFβtrap, IL-15 or IL-12, combined with an immune checkpoint inhibitor such as αPD-L1, would provide tumour-localized immunomodulation to improve CAR-T cell functionality. Here we engineer CAR-T cells to secrete TGFβtrap, IL-15 or IL-12 molecules fused to αPD-L1 scFv and assess in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR-T cells engineered with αPD-L1-IL-12 are superior in safety and efficacy compared with CAR-T cells alone and those engineered with αPD-L1 fused with TGFβtrap or IL-15. Further, αPD-L1-IL-12 engineered CAR-T cells improve T cell trafficking and tumour infiltration, and localize IFNγ production, TME modulation and antitumour responses, with reduced systemic inflammation-associated toxicities. We believe our αPD-L1-IL-12 engineering strategy presents an opportunity to improve CAR-T cell clinical efficacy and safety across multiple solid tumour types.

      Author Info: (1) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine o

      Author Info: (1) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (2) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (3) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (4) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (5) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (6) Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA. (7) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (8) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (9) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (10) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (11) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (12) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (13) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (14) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (15) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (16) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (17) Department of Bioengineering, Imperial College London, London, UK. (18) Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA. (19) Department of Chemical, Biological, and Materials Engineering, University of South Florida, Tampa, FL, USA. (20) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. priceman@usc.edu. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. priceman@usc.edu.

      Citation: Nat Biomed Eng 2025 Oct 1 Epub10/01/2025

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41034514

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      Antibody Mediated Inhibition of HLA/LILR Interactions Breaks Innate Immune Tolerance and Induces Antitumor Immunity Spotlight 

      (1) Panda AK (2) Natarajan K (3) Sinha S (4) Jiang J (5) Chempati S (6) Boyd LF (7) Desai PP (8) Buszko M (9) Kim YH (10) Kazmi S (11) Fisk B (12) Teke ME (13) Larrain CM (14) Remmert K (15) Blakely AM (16) Douagi I (17) Hernandez JM (18) Margulies DH (19) Shevach EM

      Cancer immunology research

      Leukocyte Ig-like receptors (LILRs) on NK cells bind HLA and inhibit the NK immune response. Panda et al. found that 2 anti-panHLA mAbs bound HLA with high affinity, and sterically hindered binding of LILR, but not other NK receptors (KIRs, NKG2A) or the TCR. These binders enhanced NK proliferation in vitro and in vivo. In a pancreatic tumor model, anti-panHLA mAbs alone decreased LILR+ tumor growth, although much less so than with NK cells also present. In patient tumors, immature LILR+ NK cells were enriched relative to in blood, and anti-panHLA mAbs increased patient NK cell NKp46 expression and immune cell inflammatory signatures ex vivo.

      Contributed by Alex Najibi

      (1) Panda AK (2) Natarajan K (3) Sinha S (4) Jiang J (5) Chempati S (6) Boyd LF (7) Desai PP (8) Buszko M (9) Kim YH (10) Kazmi S (11) Fisk B (12) Teke ME (13) Larrain CM (14) Remmert K (15) Blakely AM (16) Douagi I (17) Hernandez JM (18) Margulies DH (19) Shevach EM

      Cancer immunology research

      Leukocyte Ig-like receptors (LILRs) on NK cells bind HLA and inhibit the NK immune response. Panda et al. found that 2 anti-panHLA mAbs bound HLA with high affinity, and sterically hindered binding of LILR, but not other NK receptors (KIRs, NKG2A) or the TCR. These binders enhanced NK proliferation in vitro and in vivo. In a pancreatic tumor model, anti-panHLA mAbs alone decreased LILR+ tumor growth, although much less so than with NK cells also present. In patient tumors, immature LILR+ NK cells were enriched relative to in blood, and anti-panHLA mAbs increased patient NK cell NKp46 expression and immune cell inflammatory signatures ex vivo.

      Contributed by Alex Najibi

      ABSTRACT: Immune check-point blockade for the treatment of malignancies has been focused on reversing inhibitory pathways in T lymphocytes. Natural killer (NK) cells are a potent innate defense against tumors and virally infected cells, but their therapeutic manipulation for anti-cancer immunity has been inadequately explored. Considerable attention has been focused on approaches to blocking inhibitory receptors on NK and myeloid cells. Most effort has been directed to the killer immunoglobulin-like receptors (KIR) and CD94/NKG2A on NK cells. Another set of receptors with similar function in both NK cells and myeloid cells is the leukocyte immunoglobulin like receptors (LILR) that interact with a wide variety of HLA molecules. Using pan-anti-HLA mAbs that recognize a conserved epitopic region on HLA also seen by LILR, we investigated their functional effects in several models of tumor immunity. The pan-anti-HLA-mAbs blocked the binding of most LILRs, did not block killer cell immunoglobulin-like receptors (KIR) or CD94/NKG2A/C or TCR recognition. They also activated dysfunctional NK cells explanted from a variety of human cancers, and resulted in enhancement of tumor immunity in humanized mice. The mAbs also exert direct anti-tumor effects. These results suggest that activation of innate immunity via disruption of HLA/LILR interactions is a potent approach for control of both primary tumors and potentially tumor metastases.

      Author Info: (1) National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States. (2) National Institutes of Health, United States. (3) National Cancer Institute, Unite

      Author Info: (1) National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States. (2) National Institutes of Health, United States. (3) National Cancer Institute, United States. (4) National Institutes of Health, Bethesda, MD, United States. (5) National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States. (6) National Institutes of Health, Bethesda, MD, United States. (7) National Institutes of Health, Bethesda, MD, United States. (8) National Institutes of Health, Bethesda, MD, United States. (9) National Institutes of Health, Bethesda, MD, United States. (10) National Institutes of Health, Bethesda, MD, United States. (11) NIAID, United States. (12) The University of Texas Southwestern Medical Center, United States. (13) National Cancer Institute, Bethesda, Maryland, United States. (14) National Institutes of Health, Bethesda, MD, United States. (15) National Cancer Institute, Bethesda, MD, United States. (16) National Institutes of Health, Bethesda, MD, United States. (17) National Institutes of Health, Bethesda, MD, United States. (18) National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States. (19) National Institutes of Health, Bethesda, MD, United States.

      Citation: Cancer Immunol Res 2025 Oct 1 Epub10/01/2025

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41032026

      Tags:

      A specific gene expression program underlies antigen archiving by lymphatic endothelial cells in mammalian lymph nodes Spotlight 

      (1) Sheridan RM (2) Doan TA (3) Lucas CJ (4) Forward TS (5) Fleming I (6) Olsen VM (7) Qvale AM (8) Davenport BJ (9) Zarrella K (10) Harbell MG (11) Uecker-Martin A (12) Morrison TE (13) Hesselberth JR (14) Tamburini BAJ

      Nature communications | Free PMC Article

      Sheridan et al. identified that subcapsular sinus lymphatic endothelial cells (LECs) archive antigens for the longest duration post-immunization, and defined transcriptional signatures associated with long-term antigen archiving. Antigen-high LECs exhibited increased endo-lysosomal activity and clathrin- and caveolin-mediated endocytosis, and sequential immunization further enhanced the antigen uptake and archiving capacity of LECs. Machine learning uncovered gene modules predictive of antigen archiving across mouse and human datasets, and these were validated in a CHIKV infection-mediated impaired antigen-archiving model.

      Contributed by Shishir Pant

      (1) Sheridan RM (2) Doan TA (3) Lucas CJ (4) Forward TS (5) Fleming I (6) Olsen VM (7) Qvale AM (8) Davenport BJ (9) Zarrella K (10) Harbell MG (11) Uecker-Martin A (12) Morrison TE (13) Hesselberth JR (14) Tamburini BAJ

      Nature communications | Free PMC Article

      Sheridan et al. identified that subcapsular sinus lymphatic endothelial cells (LECs) archive antigens for the longest duration post-immunization, and defined transcriptional signatures associated with long-term antigen archiving. Antigen-high LECs exhibited increased endo-lysosomal activity and clathrin- and caveolin-mediated endocytosis, and sequential immunization further enhanced the antigen uptake and archiving capacity of LECs. Machine learning uncovered gene modules predictive of antigen archiving across mouse and human datasets, and these were validated in a CHIKV infection-mediated impaired antigen-archiving model.

      Contributed by Shishir Pant

      ABSTRACT: Lymph node (LN) lymphatic endothelial cells (LEC) actively acquire and archive foreign antigens. Here, we address questions of how LECs achieve durable antigen archiving and whether LECs with high levels of antigen express unique transcriptional programs. We use single cell sequencing in dissociated LN tissue and spatial transcriptomics to quantify antigen levels in LEC subsets and dendritic cell populations at multiple time points after immunization and determine that ceiling and floor LECs archive antigen for the longest duration. We identify, using spatial transcriptomics, antigen positive LEC-dendritic cell interactions. Using a prime-boost strategy we find increased antigen levels within LECs after a second immunization demonstrating that LEC antigen acquisition and archiving capacity can be improved over multiple exposures. Using machine learning we define a unique transcriptional program within archiving LECs that predicts LEC archiving capacity in independent mouse and human data sets. We test this modeling, showing we can predict lower levels of LEC antigen archiving in chikungunya virus-infected mice and demonstrate in vivo the accuracy of our prediction. Collectively, our findings establish unique properties of LECs and a defining transcriptional program for antigen archiving that can predict antigen archiving capacity in different disease states and organisms.

      Author Info: (1) Department of Biochemistry and Molecular Genetics, RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA. (2) Department of Medicine, Division o

      Author Info: (1) Department of Biochemistry and Molecular Genetics, RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA. (2) Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (3) Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (4) Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (5) Department of Biochemistry and Molecular Genetics, RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA. Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (6) Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (7) Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (8) Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (9) Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (10) Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (11) Department of Biochemistry and Molecular Genetics, RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA. (12) Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. (13) Department of Biochemistry and Molecular Genetics, RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA. (14) Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA. Beth.tamburini@cuanschutz.edu. Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. Beth.tamburini@cuanschutz.edu.

      Citation: Nat Commun 2025 Sep 25 16:8375 Epub09/25/2025

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40998762

      Tags:

      Eomesodermin+ CD4+ T cells are critical for curative immunotherapy outcomes

      Spotlight 

      (1) Zhang P (2) Haeseleer F (3) Waltner OG (4) Gartlan KH (5) Bhise SS (6) Minnie SA (7) Adams RC (8) Yeh AC (9) Ensbey KS (10) Legg SRW (11) Sekiguchi T (12) Atilla E (13) Nemychenkov NS (14) Nelson EL (15) Joshi T (16) Liang EC (17) Hirayama AV (18) Abe K (19) Koyama M (20) Clouston AD (21) Gauthier J (22) Furlan SN (23) Hill GR

      Immunity

      Zhang et al. demonstrated the differentiation of Type-1 regulatory T cells (Tr1) from an Eomes+IL-10- precursor state to Eomes+IL-10+ subsets with both regulatory and cytotoxic functions in bone marrow transplantation (BMT). Eomes+ CD4+ T cells were the major cytotoxic CD4+ T cell subset post BMT, mediating both GVL and anti-inflammatory effects via perforin-dependent APC depletion. In adoptive T cell therapy, Eomes+CD4+ CAR T cells adopted Tr1-like phenotypes that limited toxicity while sustaining cytolytic functions and persistence for durable tumor control. Eomes+CD4+ CD19-targeted CAR T cells were persistent in long-term survivors of B cell malignancies.

      Contributed by Shishir Pant

      (1) Zhang P (2) Haeseleer F (3) Waltner OG (4) Gartlan KH (5) Bhise SS (6) Minnie SA (7) Adams RC (8) Yeh AC (9) Ensbey KS (10) Legg SRW (11) Sekiguchi T (12) Atilla E (13) Nemychenkov NS (14) Nelson EL (15) Joshi T (16) Liang EC (17) Hirayama AV (18) Abe K (19) Koyama M (20) Clouston AD (21) Gauthier J (22) Furlan SN (23) Hill GR

      Immunity

      Zhang et al. demonstrated the differentiation of Type-1 regulatory T cells (Tr1) from an Eomes+IL-10- precursor state to Eomes+IL-10+ subsets with both regulatory and cytotoxic functions in bone marrow transplantation (BMT). Eomes+ CD4+ T cells were the major cytotoxic CD4+ T cell subset post BMT, mediating both GVL and anti-inflammatory effects via perforin-dependent APC depletion. In adoptive T cell therapy, Eomes+CD4+ CAR T cells adopted Tr1-like phenotypes that limited toxicity while sustaining cytolytic functions and persistence for durable tumor control. Eomes+CD4+ CD19-targeted CAR T cells were persistent in long-term survivors of B cell malignancies.

      Contributed by Shishir Pant

      ABSTRACT: Interleukin 10 (IL-10)-producing CD4(+) type-1 regulatory T cells (Tr1) promote immune tolerance during chronic infection, autoimmunity, and transplantation. However, specific Eomesodermin (Eomes)-dependent stages of Tr1 differentiation and function remain unclear. Using preclinical models of bone marrow transplantation (BMT), we demonstrated a Tr1 differentiation trajectory in vivo from Eomes(+)IL-10(-) to Eomes(+)IL-10(+) subsets with the acquisition of cytokine, cytolytic, and exhaustion features. The Eomes(+)CD4(+) fraction represented the dominant cytotoxic subset after BMT, mediating graft-versus-leukemia effects while limiting inflammation. In CD19-targeted chimeric antigen receptor (CAR) T cell immunotherapy, Eomes drove the same CD4(+) Tr1 phenotype that controlled cytolysis, while mitigating immune toxicity and promoting persistence. In individuals with high-grade B cell lymphomas that had long-term disease control after receiving commercial CD19-targeted CAR T cells, Eomes(+) Tr1 cells represented a stable population comprising 40%-80% of the CD4(+) CAR T cell population. Hence, Eomes controls both regulatory and cytotoxic programs in CD4(+) T cells, essential for curative immunotherapy outcomes.

      Author Info: (1) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006,

      Author Info: (1) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia. Electronic address: pzhang@fredhutch.org. (2) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (3) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (4) QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia. (5) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (6) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (7) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (8) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (9) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (10) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (11) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (12) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (13) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (14) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (15) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (16) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Division of Medical Oncology, University of Washington, Seattle, WA 98109, USA. (17) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (18) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (19) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (20) Envoi Pathology, Brisbane, QLD 4006, Australia. (21) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Division of Medical Oncology, University of Washington, Seattle, WA 98109, USA. (22) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA. (23) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Division of Medical Oncology, University of Washington, Seattle, WA 98109, USA. Electronic address: grhill@fredhutch.org.

      Citation: Immunity 2025 Oct 2 Epub10/02/2025

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41043413

      Tags:

      Vaccination-induced T cell responses maintain polyclonality with high antigen receptor avidity Spotlight 

      (1) Kocher K (2) Drost F (3) Tesfaye AM (4) Moosmann C (5) SchŸlein C (6) Grotz M (7) D'Ippolito E (8) Graw F (9) Spriewald B (10) Busch DH (11) Bogdan C (12) Tenbusch M (13) Schubert B (14) Schober K

      Science immunology

      In PBMC samples from 3x SARS-CoV-2 mRNA-vaccinated individuals, Kocher and Drost et al. used spike-specific dextramers to enrich CD8+ T cells for single-cell multiomics. The T cells were diverse and polyclonal, responded to WT and some mutated peptides, and new clonotypes arose after each vaccination. Functional avidity, measured after knock-in of spike-specific TCRs to primary T cells, was generally high and not correlated with clonal persistence or expansion. High TCR functionality and specificity for immunodominant epitopes associated with more differentiated T cell phenotypes, although stem-like cells also persisted.

      Contributed by Alex Najibi

      (1) Kocher K (2) Drost F (3) Tesfaye AM (4) Moosmann C (5) SchŸlein C (6) Grotz M (7) D'Ippolito E (8) Graw F (9) Spriewald B (10) Busch DH (11) Bogdan C (12) Tenbusch M (13) Schubert B (14) Schober K

      Science immunology

      In PBMC samples from 3x SARS-CoV-2 mRNA-vaccinated individuals, Kocher and Drost et al. used spike-specific dextramers to enrich CD8+ T cells for single-cell multiomics. The T cells were diverse and polyclonal, responded to WT and some mutated peptides, and new clonotypes arose after each vaccination. Functional avidity, measured after knock-in of spike-specific TCRs to primary T cells, was generally high and not correlated with clonal persistence or expansion. High TCR functionality and specificity for immunodominant epitopes associated with more differentiated T cell phenotypes, although stem-like cells also persisted.

      Contributed by Alex Najibi

      ABSTRACT: Clonal expansion is a hallmark of adaptive immunity and has been challenging to investigate in humans in a standardized manner compared with animal models. We studied a cohort of 29 healthy individuals who received three mRNA vaccinations against SARS-CoV-2 before a breakthrough infection. We characterized the magnitude, phenotype, and clonal composition of CD8 T cell responses against 16 epitope specificities by ELISpot; flow cytometry; and single-cell RNA, protein, and T cell receptor (TCR) sequencing. One hundred six TCRs from five epitope-specific repertoires were reexpressed and tested for peptide sensitivity. Whereas vaccination-recruited T cell repertoires were enriched for high-avidity TCRs, differential clonal expansion was not linked to fine avidity differences. Instead, maintenance of polyclonality ensured robustness in counteracting viral mutational escape through altered epitopes. Deciphering the functionality of human antigen-specific T cell repertoires instructs our understanding of human T cell biology and may guide the development of vaccines and other immunotherapies.

      Author Info: (1) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, UniversitŠtsklinikum Erlangen und Friedrich-Alexander-UniversitŠt (FAU) Erlangen-NŸrnberg, Erlang

      Author Info: (1) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, UniversitŠtsklinikum Erlangen und Friedrich-Alexander-UniversitŠt (FAU) Erlangen-NŸrnberg, Erlangen, Germany. (2) Institute of Computational Biology, Helmholtz Zentrum MŸnchen - German Research Center for Environmental Health, Neuherberg, Germany. School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany. (3) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, UniversitŠtsklinikum Erlangen und Friedrich-Alexander-UniversitŠt (FAU) Erlangen-NŸrnberg, Erlangen, Germany. Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. (4) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, UniversitŠtsklinikum Erlangen und Friedrich-Alexander-UniversitŠt (FAU) Erlangen-NŸrnberg, Erlangen, Germany. (5) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, UniversitŠtsklinikum Erlangen und Friedrich-Alexander-UniversitŠt (FAU) Erlangen-NŸrnberg, Erlangen, Germany. (6) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, UniversitŠtsklinikum Erlangen und Friedrich-Alexander-UniversitŠt (FAU) Erlangen-NŸrnberg, Erlangen, Germany. (7) Institute for Medical Microbiology, Immunology, and Hygiene, School of Medicine and Health, Technical University of Munich, Munich, Germany. German Center for Infection Research (Deutsches Zentrum fŸr Infektionsforschung, DZIF), Partner Site Munich, Munich, Germany. (8) Department of Internal Medicine 5, UniversitŠtsklinikum Erlangen and Friedrich-Alexander-UniversitŠt (FAU), Erlangen-NŸrnberg, Erlangen, Germany. Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-UniversitŠt (FAU) Erlangen-NŸrnberg and UniversitŠtsklinikum Erlangen, Erlangen, Germany. (9) Department of Internal Medicine 5, UniversitŠtsklinikum Erlangen and Friedrich-Alexander-UniversitŠt (FAU), Erlangen-NŸrnberg, Erlangen, Germany. (10) Institute for Medical Microbiology, Immunology, and Hygiene, School of Medicine and Health, Technical University of Munich, Munich, Germany. German Center for Infection Research (Deutsches Zentrum fŸr Infektionsforschung, DZIF), Partner Site Munich, Munich, Germany. (11) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, UniversitŠtsklinikum Erlangen und Friedrich-Alexander-UniversitŠt (FAU) Erlangen-NŸrnberg, Erlangen, Germany. FAU Profile Center Immunomedicine, FAU Erlangen-NŸrnberg, Erlangen, Germany. (12) FAU Profile Center Immunomedicine, FAU Erlangen-NŸrnberg, Erlangen, Germany. Institute of Clinical and Molecular Virology, UniversitŠtsklinikum Erlangen, Friedrich-Alexander-UniversitŠt (FAU) Erlangen-NŸrnberg, Erlangen, Germany. (13) Institute of Computational Biology, Helmholtz Zentrum MŸnchen - German Research Center for Environmental Health, Neuherberg, Germany. Department of Mathematics, Technical University of Munich, Garching bei MŸnchen, Germany. (14) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, UniversitŠtsklinikum Erlangen und Friedrich-Alexander-UniversitŠt (FAU) Erlangen-NŸrnberg, Erlangen, Germany. FAU Profile Center Immunomedicine, FAU Erlangen-NŸrnberg, Erlangen, Germany.

      Citation: Sci Immunol 2025 Oct 3 10:eadu6730 Epub10/03/2025

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41042909

      Tags:

      Distinct T cell functions enable efficient immunoediting and prevent tumor emergence of developing sarcomas Spotlight 

      (1) Cheung JF (2) Hunt BG (3) Wahed S (4) Cheng E (5) Connolly KA (6) Venkatesan S (7) Loza JL (8) Bansal I (9) Fagerberg E (10) Kessler EA (11) Riffard C (12) Buck J (13) Attanasio J (14) Borr ER (15) Wei W (16) William I (17) Fitzgerald B (18) Joshi NS

      Cancer cell

      Using a combination of traceable neoantigen-encoding, fluorescently tagged lentiviruses to induce sarcomagenesis following i.m. injection in GEM mice, tamoxifen-inducible neoantigen deletion, and patience to follow mouse models for many months, Cheung and Hunt et al. took on the problem of understanding immunoediting early after tumor initiation. Multi-clonal initiating events led to the presence of antigen-negative subclones, even in the absence of T cell editing, and the ability (or lack thereof) of neoantigen-targeting T cells to eliminate antigen-negative bystander cells through an IFNγ-dependent mechanism early (day 5-10 during the peak initial T cell response) after sarcomagenesis determined escape or elimination.

      Contributed by Ed Fritsch

      (1) Cheung JF (2) Hunt BG (3) Wahed S (4) Cheng E (5) Connolly KA (6) Venkatesan S (7) Loza JL (8) Bansal I (9) Fagerberg E (10) Kessler EA (11) Riffard C (12) Buck J (13) Attanasio J (14) Borr ER (15) Wei W (16) William I (17) Fitzgerald B (18) Joshi NS

      Cancer cell

      Using a combination of traceable neoantigen-encoding, fluorescently tagged lentiviruses to induce sarcomagenesis following i.m. injection in GEM mice, tamoxifen-inducible neoantigen deletion, and patience to follow mouse models for many months, Cheung and Hunt et al. took on the problem of understanding immunoediting early after tumor initiation. Multi-clonal initiating events led to the presence of antigen-negative subclones, even in the absence of T cell editing, and the ability (or lack thereof) of neoantigen-targeting T cells to eliminate antigen-negative bystander cells through an IFNγ-dependent mechanism early (day 5-10 during the peak initial T cell response) after sarcomagenesis determined escape or elimination.

      Contributed by Ed Fritsch

      ABSTRACT: T cells edit tumors by eliminating neoantigen-expressing tumor cells. Yet, how and when this is achieved remains uncertain. Using a murine sarcoma model with fluorescent neoantigens, we found that tumors developed later and in fewer T cell-sufficient mice (_53% penetrance) than T cell-deficient mice (_100%). With T cells, all emergent tumor cells had silenced neoantigens, but neoantigen-negative tumor cells were also present in every T cell-deficient mouse. This suggested silencing was necessary but not sufficient for outgrowth. Genetic removal of neoantigens restored tumor penetrance if implemented on day 5 post-tumor initiation, but not day 10, because CD8(+) and CD4(+) T cells infiltrated the tissue and eliminated most neoantigen-positive and -negative tumor cells within 8 days. Single-cell analyses on day-7 tumors showed oncogenic changes including increased proliferation and T cell-dependent upregulation of the IFN_-response gene Cd274 (PD-L1). T cell-depletion rescued both neoantigen-positive and -negative cells, while IFN_ blockade rescued only negative cells. This shows that T cells efficiently edit sarcomas of neoantigens and prevent early tumors via IFN_-independent and IFN_-dependent (bystander) mechanisms.

      Author Info: (1) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (2) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (3

      Author Info: (1) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (2) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (3) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (4) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (5) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (6) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (7) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (8) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (9) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (10) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (11) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (12) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (13) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (14) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (15) Department of Biostatistics, Yale University, New Haven, CT, USA. (16) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (17) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (18) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Electronic address: nikhil.joshi@yale.edu.

      Citation: Cancer Cell 2025 Oct 2 Epub10/02/2025

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41043437

      Tags:
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