Journal Articles

A viral-based individualized neoantigen vaccine as adjuvant treatment in resected head and neck squamous cell carcinoma: a randomized Phase I trial

Christian Ottensmeier, Jean-Pierre Delord, Ana Lalanne, Camille Jamet, Anne-Laure Le Gac, Katell Bidet Huang, Benoît Grellier, Jules Deforges, Maud Brandely, Eric Quéméneur, Bérangère Bastien, Annette Tavernaro, Gisèle Lacoste, Valérie Schoettel, Clémentine Spring-Giusti, Nathalie Silvestre, Jean-Baptiste Marchand, Sylvain Robin, Emmanuelle Dochy, Maurizio Ceppi, Alessandro Riva, Naoko Yamagata, Per Brattas, Kazuhide Onoguchi, Yoshiko Yamashita, Hugues Fontenelle, Mariana Eggert Martinez, Oliver Baker, Terry Jones, Andrew Schache, Eliane Piaggio, Kaïdre Bendjama, Olivier Lantz & Christophe Le Tourneau

Nature Communications

Christian Ottensmeier, Jean-Pierre Delord, Ana Lalanne, Camille Jamet, Anne-Laure Le Gac, Katell Bidet Huang, Benoît Grellier, Jules Deforges, Maud Brandely, Eric Quéméneur, Bérangère Bastien, Annette Tavernaro, Gisèle Lacoste, Valérie Schoettel, Clémentine Spring-Giusti, Nathalie Silvestre, Jean-Baptiste Marchand, Sylvain Robin, Emmanuelle Dochy, Maurizio Ceppi, Alessandro Riva, Naoko Yamagata, Per Brattas, Kazuhide Onoguchi, Yoshiko Yamashita, Hugues Fontenelle, Mariana Eggert Martinez, Oliver Baker, Terry Jones, Andrew Schache, Eliane Piaggio, Kaïdre Bendjama, Olivier Lantz & Christophe Le Tourneau

Nature Communications

ABSTRACT: In approximately one third of patients, resected head and neck squamous cell carcinoma will recur. We postulated that the induction of tumor neoantigen-specific T cell responses could prevent relapse. To this end, we developed TG4050, an individualized neoantigen therapeutic vaccine encoding up to 30 patient-specific predicted tumor neoantigens delivered by a Modified Vaccinia Ankara viral vector. We tested adjuvant TG4050 as single agent in a randomized phase I trial comparing treatment with TG4050 immediately after standard of care adjuvant therapy versus watchful waiting and treatment with TG4050 after recurrence (NCT04183166). The primary endpoint was safety, secondary endpoints included feasibility and efficacy, and immunogenicity was exploratory. TG4050 was well tolerated. Of 16 evaluable patients randomized the immediate treatment arm, none relapsed after a median follow-up of 30 months, while 3 of 16 relapsed in the control arm. T cell responses to vaccine neoantigens were detected in 73.3% of patients treated with TG4050 immediately, with a median of 3 neoantigens per responder. These responses were maintained throughout treatment and persisted for over one year after the last dose. Vaccine neoantigen-specific CD8+ T cells had an effector phenotype, displayed high expression of cytotoxic and tissue-resident markers, were polyclonal and comprised both de novo responses and amplification of pre-existing tumor-infiltrating T cell clones. Together, these translational data are consistent with the hypothesis in which single-agent delivery of TG4050 induces long-lasting tumor neoantigen-specific cytotoxic T cell responses that can prevent tumor recurrence.

Author Info:

Author Info:

Citation: Nat com 2026

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Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits

(1) Zhu R (2) Dann E (3) Yan J (4) Reyes Retana J (5) Goto R (6) Guitche RC (7) Brixi L (8) Ota M (9) Hartman A (10) Roth TL (11) Satpathy AT (12) Pritchard JK (13) Marson A

Cell

(1) Zhu R (2) Dann E (3) Yan J (4) Reyes Retana J (5) Goto R (6) Guitche RC (7) Brixi L (8) Ota M (9) Hartman A (10) Roth TL (11) Satpathy AT (12) Pritchard JK (13) Marson A

Cell

ABSTRACT: Gene regulatory networks encode the fundamental logic of cellular functions, but systematic network mapping remains challenging, especially in cell states relevant to human biology and disease. Here, we perturbed all expressed genes across 22 million primary human CD4(+) T cells from four donors and developed a probe-based perturb-seq platform to measure the transcriptome effects in cells at rest and after stimulation. These data allowed us to map genes regulating immune pathways, including previously uncharacterized regulators of cytokine production. Importantly, active regulators and the gene programs they control changed dramatically across stimulation conditions. Perturbation signatures enabled us to model T cell states observed in population-scale transcriptomic atlases, nominating regulators of T cell polarization and of age-related phenotypes. Finally, we leveraged perturb-seq to implicate context-specific gene regulatory pathways in autoimmune disease risk. Our study provides a foundational resource and new approaches to decode T cell function and human immune traits.

Author Info: (1) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: ronghui.zhu@gladston

Author Info: (1) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: ronghui.zhu@gladstone.ucsf.edu. (2) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: emmadann@stanford.edu. (3) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (4) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (5) Department of Biomedical Data Science, Stanford University, Stanford, CA, USA. (6) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; University of San Francisco, San Francisco, CA, USA. (7) Department of Genetics, Stanford University, Stanford, CA, USA. (8) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA; Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. (9) Department of Genetics, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA; Arc Institute, Palo Alto, CA, USA. (10) Department of Pathology, Stanford University, Stanford, CA, USA; Arc Institute, Palo Alto, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Weill Foundation West Coast Cancer Hub, Stanford, CA, USA. (11) Department of Genetics, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Weill Foundation West Coast Cancer Hub, Stanford, CA, USA. (12) Department of Genetics, Stanford University, Stanford, CA, USA; Department of Biology, Stanford University, Stanford, CA, USA. Electronic address: pritch@stanford.edu. (13) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Weill Foundation West Coast Cancer Hub, Stanford, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA. Electronic address: alex.marson@gladstone.ucsf.edu.

Citation: Cell 2026 Aug 28 Epub08/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42664972

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Engineered human iPSC-derived dendritic cells dressed with tumor MHC complexes as a cancer vaccine

(1) Xu H (2) Kamei C (3) Gškbuget D (4) Du J (5) Barrero M (6) Wang L (7) Iwamoto Y (8) Soriano JM (9) Godding K (10) Wang B (11) Kwek SS (12) Nistor GI (13) Keirstead HS (14) Fong L (15) Kaneko S (16) Gaensler KML (17) Blelloch R

Cell stem cell

(1) Xu H (2) Kamei C (3) Gškbuget D (4) Du J (5) Barrero M (6) Wang L (7) Iwamoto Y (8) Soriano JM (9) Godding K (10) Wang B (11) Kwek SS (12) Nistor GI (13) Keirstead HS (14) Fong L (15) Kaneko S (16) Gaensler KML (17) Blelloch R

Cell stem cell

Autologous-derived dendritic cells (DCs) are a promising source for cell-based cancer vaccines. However, their therapeutic potential is challenged by the number and quality produced and the diversity of antigens presented. To address these limitations, we present an approach that involves differentiating universal MHC-deficient human-induced pluripotent stem cells (hiPSCs) into CCR7(+) migratory DCs. These DCs are subsequently "dressed" with the full repertoire of MHC-antigen complexes derived from tumor cell membranes, transforming an allogeneic substrate into a personalized cancer vaccine product. The resulting "TumorDressed" DCs effectively activate T cells against tumor antigens. Their function is diminished when CD80/86 is deleted but significantly enhanced by the loss of PD-L1/2. PD-L1/2-null TumorDressed DCs demonstrate robust priming of anti-tumor T cell-mediated cytotoxicity both in vitro and in vivo, including against primary hematologic and solid tumors with matching patient T cells. These findings provide proof of concept for a universal, scalable, adaptable, and off-the-shelf DC cancer vaccine platform.

Author Info: (1) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, Univ

Author Info: (1) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (2) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (3) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (4) Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (5) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (6) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (7) Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. (8) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (9) AIVITA Biomedical, Irvine, CA, USA. (10) Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. (11) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (12) AIVITA Biomedical, Irvine, CA, USA. (13) AIVITA Biomedical, Irvine, CA, USA. (14) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (15) Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. (16) Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (17) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. Electronic address: robert.blelloch@ucsf.edu.

Citation: Cell Stem Cell 2026 Aug 25 Epub08/25/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42641609

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Scalable generation of hematopoietic stem cell-engineered off-the-shelf mono-specific cytotoxic T cells targeting solid tumors

(1) Zhu Y (2) Yu J (3) Kim YJ (4) Tian Y (5) Li Z (6) Chen Y (7) Lyu Z (8) Zhu E (9) Zhao AS (10) Ma N (11) Zhang C (12) Kramer A (13) Wilson M (14) Hon R (15) Wang YC (16) Lin S (17) Shen X (18) Hahn Z (19) Zhang Y (20) Wang A (21) Li YR (22) Yang L

Cell reports. Medicine

(1) Zhu Y (2) Yu J (3) Kim YJ (4) Tian Y (5) Li Z (6) Chen Y (7) Lyu Z (8) Zhu E (9) Zhao AS (10) Ma N (11) Zhang C (12) Kramer A (13) Wilson M (14) Hon R (15) Wang YC (16) Lin S (17) Shen X (18) Hahn Z (19) Zhang Y (20) Wang A (21) Li YR (22) Yang L

Cell reports. Medicine

Adoptive T cell therapy for solid tumors is limited by autologous manufacturing complexity and, in allogeneic settings, risks including graft-versus-host disease (GvHD), HLA restriction, and donor variability. We develop a scalable, feeder-free platform to differentiate gene-engineered hematopoietic stem and progenitor cells (HSPCs) into allogeneic, NY-ESO-1-specific cytotoxic T ((Allo)ESO-T) cells. Product phenotype, function, tumor homing, and safety are assessed against solid tumor models and benchmarked to peripheral blood mononuclear cell (PBMC)-derived TCR-engineered T cells. (Allo)ESO-T cells display a uniform cytotoxic phenotype, with dual tumor targeting through a transgenic TCR and natural killer receptors. Relative to PBMC-derived counterparts, (Allo)ESO-T cells show superior cytotoxicity, selective solid-tumor homing, durable killing persistence, and resilience to immune evasion. They also maintain low GvHD and cytokine release syndrome risk, while retaining stable hypoimmunogenic features. These findings establish HSPC-derived (Allo)ESO-T cells as an off-the-shelf, mono-specific cytotoxic T cell therapy with scalable manufacturing, enhanced efficacy, and improved safety, which support broad applicability of (Allo)ESO-T cells across solid tumors.

Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los A

Author Info: (1) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (2) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (3) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (4) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (5) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (6) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (7) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (8) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (9) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (10) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (11) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (12) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (13) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (14) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (15) Department of Medicine, Division of Cardiology, UCLA, Los Angeles, CA 90095, USA. (16) Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA. (17) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (18) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (19) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. (20) Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA. (21) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA. Electronic address: charlie.li@ucla.edu. (22) Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Centre of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA 90095, USA; Goodman-Luskin Microbiome Center, UCLA, Los Angeles, CA 90095, USA. Electronic address: liliyang@ucla.edu.

Citation: Cell Rep Med 2026 Aug 19 102998 Epub08/19/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42617602

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Cancer Immunotherapy Using AIRE Conditioning of the Tumor Epitopeome

(1) Chen A (2) Pulido JS (3) Tonne J (4) Metko M (5) Thompson JM (6) Sangsuwannukul T (7) Chiriboga-Yerovi MP (8) Diaz RM (9) Webb MJ (10) Huff AL (11) Moore M (12) Schuelke MR (13) Irshad S (14) Appleton E (15) Melcher A (16) Kendall B (17) Vile RG

Cancer immunology research

(1) Chen A (2) Pulido JS (3) Tonne J (4) Metko M (5) Thompson JM (6) Sangsuwannukul T (7) Chiriboga-Yerovi MP (8) Diaz RM (9) Webb MJ (10) Huff AL (11) Moore M (12) Schuelke MR (13) Irshad S (14) Appleton E (15) Melcher A (16) Kendall B (17) Vile RG

Cancer immunology research

T-cell immune tolerance is established in part through the activity of the Auto-immune Regulator (AIRE) transcription factor in the medullary thymic epithelial cells (mTEC) of the thymus. AIRE induces expression of peripheral tissue-specific self-antigens for presentation to na•ve T cells to promote activation/deletion of autoreactive T cells. This traditional role of AIRE in mTECs is to prevent autoimmunity. Herein, we demonstrate that tumors mimic the role of AIRE in mTECs to evade immune rejection. We found that AIRE induced a profile of "selfness" at the RNA and protein levels which, when presented on major histocompatibility complexes, shielded the tumor from inherently self-tolerized T cells. Moreover, we describe an in vivo immunotherapy in which engineered changes in AIRE expression in tumor cells altered their profile of selfness, exposing both AIRE-modified and parental unmodified tumor cells to T-cell attack. Therefore, by re-setting the immunological selfness of cancer cells, this AIRE-mediated immunotherapy 1) converted a highly tolerized T-cell compartment into a tumor-reactive T-cell population; 2) conferred upon non-immunogenic tumors de novo sensitivity to immune checkpoint blockade; 3) removed the need to identify potentially immunogenic tumor-associated antigens as targets for generation of T-cell responses; and 4) lead to potent T cell-mediated rejection of aggressive, immunologically cold, non-immunogenic tumors. Patient RNA-sequencing data showed that expression of AIRE predicted response to immune therapies with a strong correlation between AIRE expression and markers of T-cell receptor signaling, suggesting our studies have therapeutic translational value.

Author Info: (1) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (2) Wills Eye Hospital Philadelphia, PA United States. ROR: https://ror.org/03qygnx22 (3) Mayo Clinic Ro

Author Info: (1) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (2) Wills Eye Hospital Philadelphia, PA United States. ROR: https://ror.org/03qygnx22 (3) Mayo Clinic Rochester, Minnesota United States. ROR: https://ror.org/02qp3tb03 (4) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (5) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (6) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (7) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (8) Vyriad United States. (9) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (10) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (11) Mayo Clinic Rochester, Minnesota United States. ROR: https://ror.org/02qp3tb03 (12) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (13) King's College London London United Kingdom. ROR: https://ror.org/0220mzb33 (14) Institute of Cancer Research London United Kingdom. ROR: https://ror.org/043jzw605 (15) Institute of Cancer Research London United Kingdom. ROR: https://ror.org/043jzw605 (16) Mayo Clinic Rochester, Minnesota United States. ROR: https://ror.org/02qp3tb03 (17) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03

Citation: Cancer Immunol Res 2026 Aug 26 Epub08/26/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42644627

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Synthetic transcription factors designed by domain recombination enhance CAR T cell antitumor function

(1) Takacsi-Nagy O (2) Kasinathan S (3) Hartman A (4) Yin Y (5) Wu L (6) Chen AY (7) Moser LM (8) May AP (9) Reeder GC (10) Celallos Fuentes E (11) Kernick C (12) Lu J (13) McClellan AK (14) Raposo CJ (15) Terrall B (16) Theberath NE (17) Yan PK (18) Xu P (19) Sotillo E (20) Eyquem J (21) Mackall CL (22) Roth TL (23) Satpathy AT

Cell

(1) Takacsi-Nagy O (2) Kasinathan S (3) Hartman A (4) Yin Y (5) Wu L (6) Chen AY (7) Moser LM (8) May AP (9) Reeder GC (10) Celallos Fuentes E (11) Kernick C (12) Lu J (13) McClellan AK (14) Raposo CJ (15) Terrall B (16) Theberath NE (17) Yan PK (18) Xu P (19) Sotillo E (20) Eyquem J (21) Mackall CL (22) Roth TL (23) Satpathy AT

Cell

Human protein-coding genes evolved via rearrangement of domains from ancestral genes. We develop a scalable, evolutionarily guided method to assemble novel genes from constituent domains within a protein family, termed DESynR (domain engineered via synthesis and recombination) genes. In primary human T cells, DESynR activator protein-1 (AP-1) transcription factors (TFs) significantly outperform natural AP-1 TFs across in vitro and in vivo antitumor assays. DESynR AP-1 TFs induce broad transcriptional and epigenetic reprogramming and establish non-natural T cell states that optimize features of exhaustion, effector and cytotoxic function, and persistence-sometimes co-opting gene modules from disparate cell types. Reprogramming is primarily driven by differential regulation of established AP-1-bound regulatory elements rather than unique binding. Finally, we screen DESynR erythroblast transformation-specific (ETS) and forkhead box (FOX) TFs to support generalizability across protein families. Overall, we demonstrate that reconfiguring existing protein domains may uncover non-evolved genes that program therapeutically relevant cell states.

Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford Univer

Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (2) Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (3) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. (4) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (5) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (6) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Department of Bioengineering, Stanford University, Stanford, CA, USA. (7) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (8) Program in Immunology, Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (9) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. (10) Department of Pathology, Stanford University, Stanford, CA, USA. (11) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (12) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (13) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (14) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (15) Department of Pathology, Stanford University, Stanford, CA, USA. (16) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (17) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (18) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (19) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (20) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (21) Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (22) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. Electronic address: troth@stanford.edu. (23) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. Electronic address: satpathy@stanford.edu.

Citation: Cell 2026 Aug 19 Epub08/19/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42617595

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Tumor-induced dendritic cell deregulation perturbs T cell proliferation and predicts clinical outcome in acute lymphoblastic leukemia Spotlight 

(1) Kumar A (2) Hamane K (3) Duault C (4) Lima-Junior JR (5) Jung DH (6) Qin H (7) Salcido S (8) Huang M (9) Guo X (10) Taghi Khani A (11) Sanchez Ortiz A (12) Ghoda L (13) Marcucci G (14) Lacayo NJ (15) Sakamoto KM (16) Hurtz C (17) Carroll M (18) Tasian SK (19) Geng H (20) Ji L (21) Armenian S (22) Izraeli S (23) Wu X (24) Maecker HT (25) Swaminathan S

Cell reports. Medicine

Kumar et al. characterized the transcriptome and proteome of the DC compartment in both pediatric and adult ALL, and demonstrated that DC maturation into functional lineages was disrupted. Proliferation, antigen presentation, and cytokine production were impaired across all residual DC subsets, except progenitor/DC4 fractions, leading to a semi-mature, potentially tolerogenic phenotype with defective T cell priming. MYC overexpression in malignant lymphoblasts partly drove the disruption of DC homeostasis. A stimulated DC transcriptional signature at ALL diagnosis correlated with favorable outcomes in B-ALL, but adverse outcomes in T-ALL.

Contributed by Shishir Pant

(1) Kumar A (2) Hamane K (3) Duault C (4) Lima-Junior JR (5) Jung DH (6) Qin H (7) Salcido S (8) Huang M (9) Guo X (10) Taghi Khani A (11) Sanchez Ortiz A (12) Ghoda L (13) Marcucci G (14) Lacayo NJ (15) Sakamoto KM (16) Hurtz C (17) Carroll M (18) Tasian SK (19) Geng H (20) Ji L (21) Armenian S (22) Izraeli S (23) Wu X (24) Maecker HT (25) Swaminathan S

Cell reports. Medicine

Kumar et al. characterized the transcriptome and proteome of the DC compartment in both pediatric and adult ALL, and demonstrated that DC maturation into functional lineages was disrupted. Proliferation, antigen presentation, and cytokine production were impaired across all residual DC subsets, except progenitor/DC4 fractions, leading to a semi-mature, potentially tolerogenic phenotype with defective T cell priming. MYC overexpression in malignant lymphoblasts partly drove the disruption of DC homeostasis. A stimulated DC transcriptional signature at ALL diagnosis correlated with favorable outcomes in B-ALL, but adverse outcomes in T-ALL.

Contributed by Shishir Pant

ABSTRACT: Perturbations in dendritic cells (DCs) in B/T cell acute lymphoblastic leukemia (ALL), their cause(s) and consequence(s) on antileukemia immunity, and patient outcomes remain poorly explored. We find that maturation of DC1-6 subsets is disrupted in children and adults with ALL. Conventional DC1 and DC2 subpopulations are reduced at the expense of the progenitors and the DC4 fractions in ALL. The potential to mature, present antigens, and produce cytokines for initiating T cell surveillance appears to be impaired in every ALL DC subset. Such DC subsets are accordingly unable to induce T cell proliferation compared to DCs from healthy donors. MYC overexpression in ALL cells disrupts DC homeostasis and reduces the ability of DCs to induce T cell proliferation. Predominance of cells with transcriptional signatures typical of "stimulated DCs" predicts favorable clinical outcomes in B-ALL, while it is associated with unfavorable outcomes in T-ALL. Phenotyping DC subsets at ALL diagnosis could thus be valuable in informing treatment outcomes.

Author Info: (1) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (2) Department of Systems Biology, Beckman Research Institute of City of Hop

Author Info: (1) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (2) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (3) The Human Immune Monitoring Center (HIMC), Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA. (4) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (5) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (6) Department of Molecular and Cellular Biology, City of Hope National Medical Center, Duarte, CA 91010, USA. (7) The Hematopoietic Tissue Biorepository/Research Pathology Shared Resources, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (8) Department of Pediatrics (Hematology and Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA. (9) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (10) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (11) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (12) The Hematopoietic Tissue Biorepository/Research Pathology Shared Resources, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (13) The Hematopoietic Tissue Biorepository/Research Pathology Shared Resources, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; The Department of Hematological Malignancies Translational Science, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (14) Department of Pediatrics (Hematology and Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA. (15) Department of Pediatrics (Hematology and Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA. (16) Department of Basic Science, Division of Cancer Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA. (17) Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (18) Division of Oncology and Center for Childhood Cancer Research, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. (19) Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (20) Department of Clinical Population and Public Health Sciences, University of Southern California, Los Angeles, CA 91016, USA. (21) Department of Pediatrics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (22) Schneider Children's Medical Center, Tel Aviv University, Felsenstein Research Institute, Tel Aviv, Israel. (23) Department of Molecular and Cellular Biology, City of Hope National Medical Center, Duarte, CA 91010, USA. (24) The Human Immune Monitoring Center (HIMC), Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA. (25) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Pediatrics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. Electronic address: sswaminathan@coh.org.

Citation: Cell Rep Med 2026 Jul 28 102945 Epub07/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42520804

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CCR7+ activated dendritic cells are essential for spontaneous and immunotherapy-driven anti-tumor immunity

Featured  

(1) Koufaki MA (2) Richardson E (3) Bonavita E (4) Reeves R (5) Moeini A (6) Chiang SC (7) Banyard A (8) Russo M (9) Earnshaw CH (10) Bell CR (11) Flanagan E (12) Pelly VS (13) Nebot-Bral L (14) Pidoux A (15) Dunn P (16) Sahoo S (17) Henri S (18) Malissen B (19) MacDonald AS (20) Moncaut N (21) Zelenay S

Immunity

Koufaki et al. developed murine models to label and ablate activated CCR7+ DCs (actDCs) to study their role in tumor immunity. The activated state was shared by cDC1s and cDC2s, and was essential for priming in TDLNs, using cross-presentation for actcDC1s and cross-dressing for actcDC2s. Further, absence of actDCs resulted in reduced tumor-specific CD8+ T cells and reduced antitumor responses. ActDCs were also essential for the efficacy of ICB and ACT treatment in murine tumor models.

(1) Koufaki MA (2) Richardson E (3) Bonavita E (4) Reeves R (5) Moeini A (6) Chiang SC (7) Banyard A (8) Russo M (9) Earnshaw CH (10) Bell CR (11) Flanagan E (12) Pelly VS (13) Nebot-Bral L (14) Pidoux A (15) Dunn P (16) Sahoo S (17) Henri S (18) Malissen B (19) MacDonald AS (20) Moncaut N (21) Zelenay S

Immunity

Koufaki et al. developed murine models to label and ablate activated CCR7+ DCs (actDCs) to study their role in tumor immunity. The activated state was shared by cDC1s and cDC2s, and was essential for priming in TDLNs, using cross-presentation for actcDC1s and cross-dressing for actcDC2s. Further, absence of actDCs resulted in reduced tumor-specific CD8+ T cells and reduced antitumor responses. ActDCs were also essential for the efficacy of ICB and ACT treatment in murine tumor models.

ABSTRACT: Single-cell transcriptomics identifies a convergent activation state of conventional dendritic cells (cDCs) shared by type 1 and type 2 cDCs (cDC1s and cDC2s). These activated DCs (actDCs) are characterized by co-expression of T cell-stimulating and inhibitory molecules. Here, we examined the functional contribution of actDCs to anti-tumor immunity by developing mouse models that leverage CCR7 expression to conditionally label or ablate actDCs. The capacity of cDCs to stimulate tumor-specific cytotoxic T lymphocytes (CTLs) was restricted to the actDC state. cDC1- and cDC2-derived actDCs supported CTL priming through cross-presentation and cross-dressing, respectively, with the latter occurring in a cancer type-dependent manner. actDCs were required for the activation of naive CTLs in tumor-draining lymph nodes and for sustaining effector CTL function within tumors. Consequently, ablation of actDCs impaired spontaneous tumor control and responses to immune checkpoint blockade or adoptive T cell therapy. Thus, the actDC state emerges as a critical determinant of cDC-mediated anti-tumor immunity.

Author Info: (1) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (2) Cancer Inflammation and Immunity, Cancer Research U

Author Info: (1) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (2) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (3) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (4) Computational Biology Support, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (5) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (6) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (7) Flow Cytometry, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (8) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (9) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK; Dermatology Centre, Northern Care Alliance NHS Foundation Trust & Division of Musculoskeletal and Dermatological Sciences, Manchester NIHR Biomedical Research Centre, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK. (10) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (11) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (12) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (13) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (14) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (15) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (16) Computational Biology Support, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (17) Centre d'Etude des Pathologies Respiratoires, INSERM, UMR 1100, UniversitŽ de Tours, Tours, France. (18) Centre d'Immunologie de Marseille-Luminy, INSERM, CNRS, Aix Marseille UniversitŽ, Marseille, France; Centre d'ImmunophŽnomique, INSERM, CNRS, PHENOMIN, Celphedia, Aix Marseille UniversitŽ, Marseille, France. (19) Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, UK. (20) Genome Editing and Mouse Models, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (21) Cancer Inflammation and Immunity, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK; Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, UK. Electronic address: santiago.zelenay@cruk.manchester.ac.uk.

Citation: Immunity 2026 Aug 4 Epub08/04/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42551427

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Dendritic cell circadian clocks shape memory CD8+ T cell differentiation

Spotlight 

(1) Vleeshouwers W (2) van Duikeren S (3) de Graaf JF (4) Veerkamp DMB (5) Linger ME (6) Jorritsma SHT (7) Myeni SK (8) Kervezee L (9) Arens R

Science advances | Free PMC Article

Vleeshouwers et al. showed that the time of antigen encounter determines the differentiation of antigen-specific CD8+ T cells and antiviral immunity. In mice vaccinated with mRNA-1273, active-phase (dark period for mice [nocturnal]) immunization favored progenitor-like memory CD8+ T cells and enhanced T cell-mediated protection against SARS-CoV-2 infection, whereas resting-phase vaccination skewed toward effector-memory phenotypes. The molecular circadian clock in DCs, rather than in CD8+ T cells, regulated time-of-day-dependent CD8+ T cell differentiation and function through CD70–CD27 costimulatory signaling, independent of CD28.

Contributed by Shishir Pant

(1) Vleeshouwers W (2) van Duikeren S (3) de Graaf JF (4) Veerkamp DMB (5) Linger ME (6) Jorritsma SHT (7) Myeni SK (8) Kervezee L (9) Arens R

Science advances | Free PMC Article

Vleeshouwers et al. showed that the time of antigen encounter determines the differentiation of antigen-specific CD8+ T cells and antiviral immunity. In mice vaccinated with mRNA-1273, active-phase (dark period for mice [nocturnal]) immunization favored progenitor-like memory CD8+ T cells and enhanced T cell-mediated protection against SARS-CoV-2 infection, whereas resting-phase vaccination skewed toward effector-memory phenotypes. The molecular circadian clock in DCs, rather than in CD8+ T cells, regulated time-of-day-dependent CD8+ T cell differentiation and function through CD70–CD27 costimulatory signaling, independent of CD28.

Contributed by Shishir Pant

ABSTRACT: Circadian rhythms regulate diverse immune processes, yet how they influence memory CD8(+) T cell differentiation remains unclear. Here, we show that the time of day of antigen encounter shapes CD8(+) T cell fate and antiviral immunity. Immunization during the active phase promotes the generation of progenitor-like memory CD8(+) T cells and enhances T cell-mediated protection upon viral challenge. Mechanistically, dendritic cell-intrinsic circadian clocks regulate expression of the costimulatory ligand CD70, thereby directing T cell differentiation. These findings uncover a dendritic cell-mediated circadian mechanism that governs memory T cell fate decisions and suggest that aligning immune priming with circadian time may be leveraged to optimize T cell immunity.

Author Info: (1) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (2) Department of Immunology, Leiden University Medical Center, Alb

Author Info: (1) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (2) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (3) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (4) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (5) Leiden University Center for Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (6) Leiden University Center for Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (7) Leiden University Center for Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. (8) Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands. (9) Department of Immunology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

Citation: Sci Adv 2026 Jul 31 12:eaeh3719 Epub07/31/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42536728

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CD4+ T cells play distinct roles during the priming versus effector phases of immune checkpoint therapy-dependent tumor elimination by CD8+ T cells Featured  

(1) Ameh S (2) Theisen DJ (3) Thapa M (4) Turner JS (5) Rangarajan A (6) Nelson CA (7) Schmitz AJ (8) Song Y (9) Medrano RFV (10) Arthur CD (11) White JM (12) Sheehan KCF (13) Fremont DH (14) Ellebedy AH (15) Sultan H (16) Schreiber RD

Cancer immunology research

Ameh et al. studied the role of CD4+ T cells in mouse models during ICB treatment. CD4+ T cells were crucial for priming and effector phases to induce tumor rejection. During the effector phase, CD4+ T cells helped reinvigorate tumor-specific CD8+ T cells. CD40/CD40L signaling was vital for CD4+ T cell function during priming, while IL-2 and IFNγ were necessary for antitumor CD8+ T cell responses during the effector phase.

(1) Ameh S (2) Theisen DJ (3) Thapa M (4) Turner JS (5) Rangarajan A (6) Nelson CA (7) Schmitz AJ (8) Song Y (9) Medrano RFV (10) Arthur CD (11) White JM (12) Sheehan KCF (13) Fremont DH (14) Ellebedy AH (15) Sultan H (16) Schreiber RD

Cancer immunology research

Ameh et al. studied the role of CD4+ T cells in mouse models during ICB treatment. CD4+ T cells were crucial for priming and effector phases to induce tumor rejection. During the effector phase, CD4+ T cells helped reinvigorate tumor-specific CD8+ T cells. CD40/CD40L signaling was vital for CD4+ T cell function during priming, while IL-2 and IFNγ were necessary for antitumor CD8+ T cell responses during the effector phase.

ABSTRACT: It is well established that CD4⁺ T cells play a critical role in facilitating immune checkpoint therapy (ICT). Although CD4+ T-cell function in lymph nodes during CD8⁺ T-cell priming has been well investigated, their requirement at the effector phase in the tumor is only now beginning to be appreciated. Herein, we used our major histocompatibility complex class II-negative (MHC-II-) sarcoma models to confirm that CD4⁺ T cells are essential not only during T-cell priming, but also to maintain T-cell effector function within the tumor. Depleting CD4⁺ T cells at the effector phase, after CD8+ T-cell priming had occurred, abolished ICT-induced tumor rejection despite the detection of tumor-specific CD8⁺ T cells and their intratumoral accumulation. CD4⁺ T cells were required for functional reinvigoration of CD8⁺ tumor-infiltrating lymphocytes (TIL) by ICT, leading to enhanced cytokine production, expression of cytotoxicity, and reduced exhaustion-without affecting CD8+ T-cell proliferation. Mechanistically, CD4⁺ T-cell function at the effector phase did not require CD40/CD40L signaling, which is necessary for efficient priming, but rather depended on IL-2 and IFNγ. Using a TCR-mimic monoclonal antibody (1G10) specific for the dominant neoantigen:I-Aᵇ complex on antigen-presenting cells formed during T3 sarcoma challenge, we further showed that ongoing MHC-II neoantigen presentation was necessary to sustain CD4⁺ T-cell help after priming. These findings reveal temporally distinct requirements for CD4⁺ T-cell help and establish a need for continuous CD4⁺/CD8⁺ T-cell cooperation as a prerequisite for anti-PD-1/anti-CTLA-4 ICT efficacy against MHC-II- tumors.

Author Info: (1) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (2) Washington University in St. Louis St. Louis, MO United States. ROR: https://

Author Info: (1) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (2) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (3) Washington University in St Louis St Louis United States. (4) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (5) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (6) Washington University in St. Louis United States. ROR: https://ror.org/01yc7t268 (7) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (8) Washington University in St. Louis St. Louis, Missouri United States. ROR: https://ror.org/01yc7t268 (9) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (10) Washington University in St. Louis Saint Louis, MO United States. ROR: https://ror.org/01yc7t268 (11) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (12) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268 (13) Washington University in St. Louis St. Louis, Missouri United States. ROR: https://ror.org/01yc7t268 (14) Washington University in St. Louis St. Louis, Missouri United States. ROR: https://ror.org/01yc7t268 (15) Washington University in St. Louis St. Louis, Missouri United States. ROR: https://ror.org/01yc7t268 (16) Washington University in St. Louis St. Louis, MO United States. ROR: https://ror.org/01yc7t268

Citation: Cancer Immunol Res 2026 Jul 16 Epub07/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42462143

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