Journal Articles

Fc-optimized anti-CTLA-4 antibodies increase tumor-associated high endothelial venules and sensitize refractory tumors to PD-1 blockade

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Lucas Blanchard (1,2,5,*); Estefania Vina (1,2,5); Jerko Ljubetic (1,2); Cécile Meneur (1,2); Dorian Tarroux (1,2); Maria Baez (3); Alessandra Marino (3); Nathalie Ortega (1,2); David A. Knorr (3,4); Jeffrey V. Ravetch (3); and Jean-Philippe Girard (1,2,6,*)

Cell Reports Medicine

Blanchard and Vina et al. investigated mechanisms by which anti-CTLA-4 mAbs modulate tumor-associated high endothelial venules (TA-HEVs), which are important for supporting lymphocyte entry into tumors. In mouse models, anti-CTLA-4 Fc-derived effector function was required to increase TA-HEVs. CD4+ T cells and IFNγ were also found to be important during anti-CTLA-4 therapy. Consequently, Fc engineering of ipilimumab was necessary to increase TA-HEVs in humanized mice. Combination with anti-PD-1 increased TA-HEVs, promoted CD4+ and CD8+ T cell infiltration into tumors, and sensitized cold, refractory tumors to PD-1 blockade.

Contributed by Katherine Turner

Lucas Blanchard (1,2,5,*); Estefania Vina (1,2,5); Jerko Ljubetic (1,2); Cécile Meneur (1,2); Dorian Tarroux (1,2); Maria Baez (3); Alessandra Marino (3); Nathalie Ortega (1,2); David A. Knorr (3,4); Jeffrey V. Ravetch (3); and Jean-Philippe Girard (1,2,6,*)

Cell Reports Medicine

Blanchard and Vina et al. investigated mechanisms by which anti-CTLA-4 mAbs modulate tumor-associated high endothelial venules (TA-HEVs), which are important for supporting lymphocyte entry into tumors. In mouse models, anti-CTLA-4 Fc-derived effector function was required to increase TA-HEVs. CD4+ T cells and IFNγ were also found to be important during anti-CTLA-4 therapy. Consequently, Fc engineering of ipilimumab was necessary to increase TA-HEVs in humanized mice. Combination with anti-PD-1 increased TA-HEVs, promoted CD4+ and CD8+ T cell infiltration into tumors, and sensitized cold, refractory tumors to PD-1 blockade.

Contributed by Katherine Turner

ABSTRACT: The lack of T cells in tumors is a major hurdle to successful immune checkpoint therapy (ICT). Therefore, therapeutic strategies promoting T cell recruitment into tumors are warranted to improve the treatment efficacy. Here, we report that Fc-optimized anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies are potent re-modelers of tumor vasculature that increase tumor-associated high endothelial venules (TA-HEVs), specialized blood vessels supporting lymphocyte entry into tumors. Mechanistically, this effect is dependent on the Fc domain of anti-CTLA-4 antibodies and CD4+ T cells and involves interferon gamma (IFNγ). Unexpectedly, we find that the human anti-CTLA-4 antibody ipilimumab fails to increase TA-HEVs in a humanized mouse model. However, increasing its Fc effector function rescues the modulation of TA-HEVs, promotes CD4+ and CD8+ T cell infiltration into tumors, and sensitizes recalcitrant tumors to programmed cell death protein 1 (PD-1) blockade. Our findings suggest that Fc-optimized anti-CTLA-4 antibodies could be used to reprogram tumor vasculature in poorly immunogenic cold tumors and improve the efficacy of ICT.

Author Info: 1-Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France 2-Equipe Labellisée LIGUE 2023, Paris, France 3-Laboratory of Mo

Author Info: 1-Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France 2-Equipe Labellisée LIGUE 2023, Paris, France 3-Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY, USA 4-Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5-These authors contributed equally 6-Lead contact *Correspondence: lblanchard@rockefeller.edu, jean-philippe.girard@ipbs.fr

Citation: Cell rep med 2025

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Immunopeptidomics-guided discovery and characterization of neoantigens for personalized cancer immunotherapy Spotlight 

(1) Cai Y (2) Gong M (3) Zeng M (4) Leng F (5) Lv D (6) Guo J (7) Wang H (8) Li Y (9) Lin Q (10) Jing J (11) Zhang Y (12) Xu J (13) Li Y

Science advances | Free PMC Article

To identify novel neoantigens, Cai et al. assembled an immunopeptidomics atlas from published tumor and normal tissue datasets. Non-canonical (non-coding; 15%) and canonical (85%) peptides exhibited similar tissue distribution and presentation. Tumor-derived peptides exhibited differential features compared to normal tissue-derived peptides, such as positively charged residues and basic AA anchors. Cancer- and tissue-specific machine learning models identified 2,523 immunogenic tumor-specific peptides (41% noncanonical), most of which were patient-specific. Three highly ranked candidate pan-cancer peptides induced proliferation and antitumor cytotoxic activity in T cells.

Contributed by Morgan Janes

(1) Cai Y (2) Gong M (3) Zeng M (4) Leng F (5) Lv D (6) Guo J (7) Wang H (8) Li Y (9) Lin Q (10) Jing J (11) Zhang Y (12) Xu J (13) Li Y

Science advances | Free PMC Article

To identify novel neoantigens, Cai et al. assembled an immunopeptidomics atlas from published tumor and normal tissue datasets. Non-canonical (non-coding; 15%) and canonical (85%) peptides exhibited similar tissue distribution and presentation. Tumor-derived peptides exhibited differential features compared to normal tissue-derived peptides, such as positively charged residues and basic AA anchors. Cancer- and tissue-specific machine learning models identified 2,523 immunogenic tumor-specific peptides (41% noncanonical), most of which were patient-specific. Three highly ranked candidate pan-cancer peptides induced proliferation and antitumor cytotoxic activity in T cells.

Contributed by Morgan Janes

ABSTRACT: Neoantigens have emerged as ideal targets for personalized cancer immunotherapy. We depict the pan-cancer peptide atlas by comprehensively collecting immunopeptidomics from 531 samples across 14 cancer and 29 normal tissues, and identify 389,165 canonical and 70,270 noncanonical peptides. We reveal that noncanonical peptides exhibit comparable presentation levels as canonical peptides across cancer types. Tumor-specific peptides exhibit significantly distinct biochemical characteristics compared with those observed in normal tissues. We further propose an immunopeptidomic-guided machine learning-based neoantigen screening pipeline (MaNeo) to prioritize neo-peptides as immunotherapy targets. Benchmark analysis reveals MaNeo results in the accurate identification of shared and tumor-specific canonical and noncanonical neo-peptides. Last, we use MaNeo to detect and validate three neo-peptides in cancer cell lines, which can effectively induce increased proliferation of active T cells and T cell responses to kill cancer cells but not damage healthy cells. The pan-cancer peptide atlas and proposed MaNeo pipeline hold great promise for the discovery of canonical and noncanonical neoantigens for cancer immunotherapies.

Author Info: (1) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. (2) De

Author Info: (1) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. (2) Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China. (3) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. (4) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. (5) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. (6) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), School of Interdisciplinary Medicine and Engineering, Harbin Medical University, Harbin, Heilongjiang 150081, China. (7) Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China. (8) The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China. (9) Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150040, China. (10) Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150040, China. (11) Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China. (12) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. (13) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), School of Interdisciplinary Medicine and Engineering, Harbin Medical University, Harbin, Heilongjiang 150081, China. Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150040, China.

Citation: Sci Adv 2025 May 23 11:eadv6445 Epub05/21/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40397742

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Mature tertiary lymphoid structures evoke intra-tumoral T and B cell responses via progenitor exhausted CD4+ T cells in head and neck cancer

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(1) Li H (2) Zhang MJ (3) Zhang B (4) Lin WP (5) Li SJ (6) Xiong D (7) Wang Q (8) Wang WD (9) Yang QC (10) Huang CF (11) Deng WW (12) Sun ZJ

Nature communications | Free PMC Article

Li and Zhang et al. reported the presence of stem-like T cells and B cells at various stages of tertiary lymphoid structure (TLS) maturation in patient HNSCC tumors. Mature TLS (mTLS) were enriched for stem-like and functional CD8+ T cells, CD4+ Texprog/Tfh cells, and diverse subtypes of B cells and plasma cells. Immature TLS displayed an enrichment of B cells without concurrent plasma cells. Spatial transcriptomics confirmed the presence of triads of CD4+ Texprog/Tfh cells with DCs and B cells, suggesting mTLSs have a role in B cell maturation and effector memory CD8+ T cell generation. The presence of mTLSs was associated with response to ICB therapy in HNSCC.

Contributed by Shishir Pant

(1) Li H (2) Zhang MJ (3) Zhang B (4) Lin WP (5) Li SJ (6) Xiong D (7) Wang Q (8) Wang WD (9) Yang QC (10) Huang CF (11) Deng WW (12) Sun ZJ

Nature communications | Free PMC Article

Li and Zhang et al. reported the presence of stem-like T cells and B cells at various stages of tertiary lymphoid structure (TLS) maturation in patient HNSCC tumors. Mature TLS (mTLS) were enriched for stem-like and functional CD8+ T cells, CD4+ Texprog/Tfh cells, and diverse subtypes of B cells and plasma cells. Immature TLS displayed an enrichment of B cells without concurrent plasma cells. Spatial transcriptomics confirmed the presence of triads of CD4+ Texprog/Tfh cells with DCs and B cells, suggesting mTLSs have a role in B cell maturation and effector memory CD8+ T cell generation. The presence of mTLSs was associated with response to ICB therapy in HNSCC.

Contributed by Shishir Pant

ABSTRACT: Tumor tertiary lymphoid structures (TLS), especially mature TLS (mTLS), have been associated with better prognosis and improved responses to immune checkpoint blockade (ICB), but the underlying mechanisms remain incompletely understood. Here, by performing single-cell RNA, antigen receptor sequencing and spatial transcriptomics on tumor tissue from head and neck squamous cell carcinoma (HNSCC) patients with different statuses of TLS, we observe that mTLS are enriched with stem-like T cells, and B cells at various maturation stages. Notably, progenitor exhausted CD4(+) T cells, with features resembling follicular helper T cells, support these responses, by activating B cells to produce plasma cells in the germinal center, and interacting with DC-LAMP(+) dendritic cells to support CD8(+) T cell activation. Conversely, non-mTLS tumors do not promote local anti-tumor immunity which is abundant of immunosuppressive cells or a lack of stem-like B and T cells. Furthermore, patients with mTLS manifest improved overall survival and response to ICB compared to those with non-mTLS. Overall, our study provides insights into mechanisms underlying mTLS-mediated intra-tumoral immunity events against cancer.

Author Info: (1) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, Sch

Author Info: (1) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. Department of Oral Maxillofacial-Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China. (2) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (3) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (4) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (5) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (6) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (7) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (8) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (9) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (10) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. (11) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. dww@whu.edu.cn. Department of Oral Maxillofacial-Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China. dww@whu.edu.cn. (12) State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. sunzj@whu.edu.cn. Department of Oral Maxillofacial-Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China. sunzj@whu.edu.cn.

Citation: Nat Commun 2025 May 7 16:4228 Epub05/07/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40335494

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CD8+ T cell-derived CD40L mediates noncanonical cytotoxicity in CD40-expressing cancer cells

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(1) Schiele P (2) Japp AS (3) Stark R (4) Sattelberg JJ (5) Nikolaou C (6) Kornhuber G (7) Abbasi P (8) Ding N (9) Rosnev S (10) Meinke S (11) Mühle K (12) Loyal L (13) Braun J (14) Dingeldey M (15) Durlanik S (16) Matzmohr N (17) Ponikwicka-Tyszko D (18) Wolczynski S (19) Rahman NA (20) Taniuchi I (21) Schlickeiser S (22) Giesecke-Thiel C (23) Blankenstein T (24) Na IK (25) Thiel A (26) Frentsch M

Science advances | Free PMC Article

Schiele, Japp, Stark et al. showed that up to half of tumor-specific CD8+ T cells in mice bearing CD40-expressing cancers were CD40L+. CD40L-/-CD8+ T cells transferred into RAG1-/- mice failed to reject CD40+ tumor cells, even when cotransferred with WT CD4+ T cells that expressed CD40L upon activation. CD40 KO, but not CD40L KO, mice rejected CD40+ tumor cells. Human CD40L+CD8+ T cells induced caspase-mediated death of CD40+ human carcinoma cell lines in vitro. A six-gene signature predictive of resistance to CD40-signaled cell death was identified in RCC cell lines and was shown to be associated with a lower survival rate in patients with RCC.

Contributed by Paula Hochman

(1) Schiele P (2) Japp AS (3) Stark R (4) Sattelberg JJ (5) Nikolaou C (6) Kornhuber G (7) Abbasi P (8) Ding N (9) Rosnev S (10) Meinke S (11) Mühle K (12) Loyal L (13) Braun J (14) Dingeldey M (15) Durlanik S (16) Matzmohr N (17) Ponikwicka-Tyszko D (18) Wolczynski S (19) Rahman NA (20) Taniuchi I (21) Schlickeiser S (22) Giesecke-Thiel C (23) Blankenstein T (24) Na IK (25) Thiel A (26) Frentsch M

Science advances | Free PMC Article

Schiele, Japp, Stark et al. showed that up to half of tumor-specific CD8+ T cells in mice bearing CD40-expressing cancers were CD40L+. CD40L-/-CD8+ T cells transferred into RAG1-/- mice failed to reject CD40+ tumor cells, even when cotransferred with WT CD4+ T cells that expressed CD40L upon activation. CD40 KO, but not CD40L KO, mice rejected CD40+ tumor cells. Human CD40L+CD8+ T cells induced caspase-mediated death of CD40+ human carcinoma cell lines in vitro. A six-gene signature predictive of resistance to CD40-signaled cell death was identified in RCC cell lines and was shown to be associated with a lower survival rate in patients with RCC.

Contributed by Paula Hochman

ABSTRACT: T cells and their effector functions, in particular the canonical cytotoxicity of CD8(+) T cells involving perforin, granzymes, Fas ligand (FasL), and tumor necrosis factor related apoptosis inducing ligand (TRAIL), are crucial for tumor immunity. Here, we reveal a previously unidentified mechanism by which CD40L-expressing CD8(+) T cells induce cytotoxicity in cancer cells. In murine models, up to 50% of tumor-specific CD8(+) T cells expressed CD40L, and conditional CD40L ablation in CD8(+) T cells alone led to tumor formation. Mechanistically, CD40L(+)CD8(+) T cells can induce cell death in CD40-expressing cancer cells by triggering caspase-8 activation. We demonstrate that a gene signature for resistance to CD40 signaling-induced cell death strongly correlates with worse survival in different human cancer cohorts. Our results introduce CD40L as a rather counterintuitive, noncanonical cytotoxic factor that complements the capabilities of CD8(+) T cells to combat cancers and has the potential to enhance the efficacy of immunotherapies.

Author Info: (1) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Ger

Author Info: (1) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (2) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. Captain T Cell GmbH, 12529 Berlin, Germany. (3) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. Tissue Immunology, BIH Center for Regenerative Therapies, CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (4) Max-DelbrŸck-Center for Molecular Medicine and Institute for Immunology, CharitŽ-UniversitŠtsmedizin Berlin, 13125 Berlin, Germany. (5) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (6) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (7) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (8) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (9) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (10) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (11) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (12) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. Si-M/"Der Simulierte Mensch," Technische UniversitŠt Berlin and CharitŽ - UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (13) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. Si-M/"Der Simulierte Mensch," Technische UniversitŠt Berlin and CharitŽ - UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (14) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. Si-M/"Der Simulierte Mensch," Technische UniversitŠt Berlin and CharitŽ - UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (15) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (16) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (17) Institute of Biomedicine, University of Turku, 20520 Turku, Finland. Department of Biology and Pathology of Human Reproduction, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-748 Olsztyn, Poland. (18) Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, 15-276 Bialystok, Poland. (19) Institute of Biomedicine, University of Turku, 20520 Turku, Finland. Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, 15-276 Bialystok, Poland. (20) RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan. (21) Institute for Medical Immunology, CharitŽ-UniversitŠtsmedizin Berlin, Corporate members of Freie UniversitŠt Berlin and Humboldt-UniversitŠt zu Berlin, Berlin, Germany. (22) Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. (23) Max-DelbrŸck-Center for Molecular Medicine and Institute for Immunology, CharitŽ-UniversitŠtsmedizin Berlin, 13125 Berlin, Germany. (24) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. Department of Hematology, Oncology and Tumor Immunology, and ECRC Experimental and Clinical Research Center, both CharitŽ-UniversitŠtsmedizin Berlin, Corporate members of Freie UniversitŠt Berlin and Humboldt-UniversitŠt zu Berlin, Berlin, Germany. German Cancer Consortium (DKTK), Berlin, Germany. ECRC Experimental and Clinical Research Center, Corporate Member of Freie UniversitŠt Berlin and Humboldt UniversitŠt zu Berlin, CharitŽ UniversitŠtsmedizin Berlin, Berlin, Germany. (25) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. Si-M/"Der Simulierte Mensch," Technische UniversitŠt Berlin and CharitŽ - UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. (26) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany. Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at CharitŽ-UniversitŠtsmedizin Berlin, 13353 Berlin, Germany.

Citation: Sci Adv 2025 May 23 11:eadr9331 Epub05/21/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40397730

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Sensitizing solid tumors to CAR-mediated cytotoxicity by lipid nanoparticle delivery of synthetic antigens Spotlight 

(1) Gamboa L (2) Zamat AH (3) Thiveaud CA (4) Lee HJ (5) Kulaksizoglu E (6) Zha Z (7) Campbell NS (8) Chan CS (9) F‡brega S (10) Oliver SA (11) Su FY (12) Phuengkham H (13) Vanover D (14) Peck HE (15) Sivakumar A (16) Dahotre SN (17) Harris AM (18) Santangelo PJ (19) Kwong GA

Nature cancer

Gamboa and Zamat et al. optimized LNPs to deliver a synthetic antigen (the camelid VHH) to tumors, enabling recognition by anti-VHH CAR T cells. Anti-VHH CAR T cells responded to VHH+ tumor cell lines, but not VHH- human PBMCs, and were well tolerated in naive mice. Intratumoral VHH-LNP injection led to tumor cell VHH expression, and subsequent adoptive transfer of anti-VHH CAR T cells controlled tumor growth and prompted antigen spreading, restricting growth of even VHH- parental tumor cells. This treatment strategy had superior efficacy to standard CAR T cells (anti-HER2 CAR T) in mixed antigen (e.g., HER2+/-) models.

Contributed by Alex Najibi

(1) Gamboa L (2) Zamat AH (3) Thiveaud CA (4) Lee HJ (5) Kulaksizoglu E (6) Zha Z (7) Campbell NS (8) Chan CS (9) F‡brega S (10) Oliver SA (11) Su FY (12) Phuengkham H (13) Vanover D (14) Peck HE (15) Sivakumar A (16) Dahotre SN (17) Harris AM (18) Santangelo PJ (19) Kwong GA

Nature cancer

Gamboa and Zamat et al. optimized LNPs to deliver a synthetic antigen (the camelid VHH) to tumors, enabling recognition by anti-VHH CAR T cells. Anti-VHH CAR T cells responded to VHH+ tumor cell lines, but not VHH- human PBMCs, and were well tolerated in naive mice. Intratumoral VHH-LNP injection led to tumor cell VHH expression, and subsequent adoptive transfer of anti-VHH CAR T cells controlled tumor growth and prompted antigen spreading, restricting growth of even VHH- parental tumor cells. This treatment strategy had superior efficacy to standard CAR T cells (anti-HER2 CAR T) in mixed antigen (e.g., HER2+/-) models.

Contributed by Alex Najibi

ABSTRACT: Chimeric antigen receptor (CAR) T cell immunotherapy relies on CAR targeting of tumor-associated antigens; however, heterogenous antigen expression, interpatient variation and off-tumor expression by healthy cells remain barriers. Here we develop synthetic antigens to sensitize solid tumors for recognition and elimination by CAR T cells. Unlike tumor-associated antigens, we design synthetic antigens that are orthogonal to endogenous proteins to eliminate off-tumor targeting and that have a small genetic footprint to facilitate efficient tumor delivery to tumors by lipid nanoparticles. Using a camelid single-domain antibody (VHH) as a synthetic antigen, we show that adoptive transfer of anti-VHH CAR T cells to female mice bearing VHH-expressing tumors reduced tumor burden in multiple syngeneic and xenograft models of cancer, improved survival, induced epitope spread, protected against tumor rechallenge and mitigated antigen escape in heterogenous tumors. Our work supports the in situ delivery of synthetic antigens to treat antigen-low or antigen-negative tumors with CAR T cells.

Author Info: (1) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (2) Wallace H. Coulter Department of Bi

Author Info: (1) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (2) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (3) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (4) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (5) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (6) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (7) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (8) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (9) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (10) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (11) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (12) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (13) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (14) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (15) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (16) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (17) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (18) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. (19) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA. gkwong@gatech.edu. Parker H. Petit Institute of Bioengineering and Bioscience, Atlanta, GA, USA. gkwong@gatech.edu. Institute for Matter and Systems, Georgia Institute of Technology, Atlanta, GA, USA. gkwong@gatech.edu. The Georgia Immunoengineering Consortium, Emory University and Georgia Tech, Atlanta, GA, USA. gkwong@gatech.edu. Winship Cancer Institute, Emory University, Atlanta, GA, USA. gkwong@gatech.edu.

Citation: Nat Cancer 2025 May 16 Epub05/16/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40379831

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Tumor antigens preferentially derive from unmutated genomic sequences in melanoma and non-small cell lung cancer Featured  

(1) Apavaloaei A (2) Zhao Q (3) Hesnard L (4) Cahuzac M (5) Durette C (6) Larouche JD (7) Hardy MP (8) Vincent K (9) Brochu S (10) Laverdure JP (11) Lanoix J (12) Courcelles M (13) Gendron P (14) Lajoie M (15) Ruiz Cuevas MV (16) Kina E (17) Perrault J (18) Humeau J (19) Ehx G (20) Lemieux S (21) Watson IR (22) Speiser DE (23) Bassani-Sternberg M (24) Thibault P (25) Perreault C

Nature cancer

Apavaloaei et al. analyzed tumor cell surface expression of MHC-I-associated peptides (MAPs) derived from tumor antigens (TAs) in melanoma and non-small cell lung cancer. The vast majority of detected MAPs were from unmutated genomic regions. Mutated tumor-specific antigens were limited due to low RNA expression and being outside of MAP hotspots. High numbers of unmutated TAs were identified. Responders to anti-PD-1 treatment exhibited a decrease in aberrantly-expressed tumor-specific antigens (aeTSAs), which were found to be highly immunogenic, cancer-specific, and shared between patients.

(1) Apavaloaei A (2) Zhao Q (3) Hesnard L (4) Cahuzac M (5) Durette C (6) Larouche JD (7) Hardy MP (8) Vincent K (9) Brochu S (10) Laverdure JP (11) Lanoix J (12) Courcelles M (13) Gendron P (14) Lajoie M (15) Ruiz Cuevas MV (16) Kina E (17) Perrault J (18) Humeau J (19) Ehx G (20) Lemieux S (21) Watson IR (22) Speiser DE (23) Bassani-Sternberg M (24) Thibault P (25) Perreault C

Nature cancer

Apavaloaei et al. analyzed tumor cell surface expression of MHC-I-associated peptides (MAPs) derived from tumor antigens (TAs) in melanoma and non-small cell lung cancer. The vast majority of detected MAPs were from unmutated genomic regions. Mutated tumor-specific antigens were limited due to low RNA expression and being outside of MAP hotspots. High numbers of unmutated TAs were identified. Responders to anti-PD-1 treatment exhibited a decrease in aberrantly-expressed tumor-specific antigens (aeTSAs), which were found to be highly immunogenic, cancer-specific, and shared between patients.

ABSTRACT: Melanoma and non-small cell lung cancer (NSCLC) display exceptionally high mutational burdens. Hence, immune targeting in these cancers has primarily focused on tumor antigens (TAs) predicted to derive from nonsynonymous mutations. Using comprehensive proteogenomic analyses, we identified 589 TAs in cutaneous melanoma (n = 505) and NSCLC (n = 90). Of these, only 1% were derived from mutated sequences, which was explained by a low RNA expression of most nonsynonymous mutations and their localization outside genomic regions proficient for major histocompatibility complex (MHC) class I-associated peptide generation. By contrast, 99% of TAs originated from unmutated genomic sequences specific to cancer (aberrantly expressed tumor-specific antigens (aeTSAs), n = 220), overexpressed in cancer (tumor-associated antigens (TAAs), n = 165) or specific to the cell lineage of origin (lineage-specific antigens (LSAs), n = 198). Expression of aeTSAs was epigenetically regulated, and most were encoded by noncanonical genomic sequences. aeTSAs were shared among tumor samples, were immunogenic and could contribute to the response to immune checkpoint blockade observed in previous studies, supporting their immune targeting across cancers.

Author Info: (1) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Cana

Author Info: (1) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (2) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (3) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (4) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (5) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (6) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (7) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (8) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (9) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (10) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (11) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (12) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (13) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (14) Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada. (15) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, Quebec, Canada. (16) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (17) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (18) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (19) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Laboratory of Hematology, GIGA Institute, University of Liege, Liege, Belgium. Walloon Excellence in Life Sciences and Biotechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium. (20) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, Quebec, Canada. (21) Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada. Department of Biochemistry, McGill University, Montreal, Quebec, Canada. (22) Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. (23) Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland. (24) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. pierre.thibault@umontreal.ca. Department of Chemistry, University of Montreal, Montreal, Quebec, Canada. pierre.thibault@umontreal.ca. (25) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. claude.perreault@umontreal.ca. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. claude.perreault@umontreal.ca.

Citation: Nat Cancer 2025 May 22 Epub05/22/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40405018

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Atezolizumab plus personalized neoantigen vaccination in urothelial cancer: a phase 1 trial Spotlight 

(1) Saxena M (2) Anker JF (3) Kodysh J (4) O'Donnell T (5) Kaminska AM (6) Meseck M (7) Hapanowicz O (8) Niglio SA (9) Salazar AM (10) Shah HR (11) Kinoshita Y (12) Brody R (13) Rubinsteyn A (14) Sebra RP (15) Bhardwaj N (16) Galsky MD

Nature cancer

Saxena, Anker, Kodysh et al. demonstrated that the personalized long-peptide neoantigen vaccine PGV001, in combination with atezolizumab, was feasible, safe, and elicited durable neoantigen-specific T cell responses in patients with urothelial cancer (UC). Introduction of anti-PD-L1 during the priming cycle, after the first three PGV001 doses, produced neoantigen-specific T cell response in 100% of evaluable participants. Among 5 patients with metastatic UC, 2 achieved an objective response to treatment, and among 4 patients treated in the adjuvant setting, 3 remained recurrence-free at a median follow-up of 39 months.

Contributed by Shishir Pant

(1) Saxena M (2) Anker JF (3) Kodysh J (4) O'Donnell T (5) Kaminska AM (6) Meseck M (7) Hapanowicz O (8) Niglio SA (9) Salazar AM (10) Shah HR (11) Kinoshita Y (12) Brody R (13) Rubinsteyn A (14) Sebra RP (15) Bhardwaj N (16) Galsky MD

Nature cancer

Saxena, Anker, Kodysh et al. demonstrated that the personalized long-peptide neoantigen vaccine PGV001, in combination with atezolizumab, was feasible, safe, and elicited durable neoantigen-specific T cell responses in patients with urothelial cancer (UC). Introduction of anti-PD-L1 during the priming cycle, after the first three PGV001 doses, produced neoantigen-specific T cell response in 100% of evaluable participants. Among 5 patients with metastatic UC, 2 achieved an objective response to treatment, and among 4 patients treated in the adjuvant setting, 3 remained recurrence-free at a median follow-up of 39 months.

Contributed by Shishir Pant

ABSTRACT: Features of constrained adaptive immunity and high neoantigen burden have been correlated with response to immune checkpoint inhibitors (ICIs). In an attempt to stimulate antitumor immunity, we evaluated atezolizumab (anti-programmed cell death protein 1 ligand 1) in combination with PGV001, a personalized neoantigen vaccine, in participants with urothelial cancer. The primary endpoints were feasibility (as defined by neoantigen identification, peptide synthesis, vaccine production time and vaccine administration) and safety. Secondary endpoints included objective response rate, duration of response and progression-free survival for participants treated in the metastatic setting, time to progression for participants treated in the adjuvant setting, overall survival and vaccine-induced neoantigen-specific T cell immunity. A vaccine was successfully prepared (median 20.3_weeks) for 10 of 12 enrolled participants. All participants initiating treatment completed the priming cycle. The most common treatment-related adverse events were grade 1 injection site reactions, fatigue and fever. At a median follow-up of 39_months, three of four participants treated in the adjuvant setting were free of recurrence and two of five participants treated in the metastatic setting with measurable disease achieved an objective response. All participants demonstrated on-treatment emergence of neoantigen-specific T cell responses. Neoantigen vaccination plus ICI was feasible and safe, meeting its endpoints, and warrants further investigation. ClinicalTrials.gov registration: NCT03359239 .

Author Info: (1) Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Medicine, Division of Hematology Oncology

Author Info: (1) Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Medicine, Division of Hematology Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) Department of Medicine, Division of Hematology Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Department of Medicine, Division of Hematology Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) New York University Langone Laura and Isaac Perlmutter Cancer Center, New York, NY, USA. (9) Oncovir, Inc., Washington, D.C., USA. (10) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11) Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (14) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) Vaccine and Cell Therapy Laboratory, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. nina.bhardwaj@mssm.edu. Department of Medicine, Division of Hematology Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. nina.bhardwaj@mssm.edu. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. nina.bhardwaj@mssm.edu. Parker Institute of Cancer Immunotherapy, San Francisco, CA, USA. nina.bhardwaj@mssm.edu. (16) Department of Medicine, Division of Hematology Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. matthew.galsky@mssm.edu.

Citation: Nat Cancer 2025 May 9 Epub05/09/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40346292

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Pancreatic cancer-restricted cryptic antigens are targets for T cell recognition

Featured  

(1) Ely ZA (2) Kulstad ZJ (3) Gunaydin G (4) Addepalli S (5) Verzani EK (6) Casarrubios M (7) Clauser KR (8) Wang X (9) Lippincott IE (10) Louvet C (11) Schmitt T (12) Kapner KS (13) Agus MP (14) Hennessey CJ (15) Cleary JM (16) Hadrup SR (17) Klaeger S (18) Su J (19) Jaeger AM (20) Wolpin BM (21) Raghavan S (22) Smith EL (23) Greenberg PD (24) Aguirre AJ (25) Abelin JG (26) Carr SA (27) Jacks T (28) Freed-Pastor WA

Science

Ely, Kulstad, et al. developed an immunopeptidomics pipeline to investigate noncanonical HLA-I-bound peptides (ncHLAp) in patient-derived organoids of pancreatic ductal carcinoma (PDAC). A subset (~30%) of detected ncHLAp were cancer-restricted (CR), which were partially shared between patients. The detected CR ncHLAp were immunogenic. Engineered CR ncHLAp-specific TCR-T cells could detect endogenous levels of expression of presented peptides in vitro, and high-avidity TCR-T cells were found to temporarily delay tumor growth in vivo.

(1) Ely ZA (2) Kulstad ZJ (3) Gunaydin G (4) Addepalli S (5) Verzani EK (6) Casarrubios M (7) Clauser KR (8) Wang X (9) Lippincott IE (10) Louvet C (11) Schmitt T (12) Kapner KS (13) Agus MP (14) Hennessey CJ (15) Cleary JM (16) Hadrup SR (17) Klaeger S (18) Su J (19) Jaeger AM (20) Wolpin BM (21) Raghavan S (22) Smith EL (23) Greenberg PD (24) Aguirre AJ (25) Abelin JG (26) Carr SA (27) Jacks T (28) Freed-Pastor WA

Science

Ely, Kulstad, et al. developed an immunopeptidomics pipeline to investigate noncanonical HLA-I-bound peptides (ncHLAp) in patient-derived organoids of pancreatic ductal carcinoma (PDAC). A subset (~30%) of detected ncHLAp were cancer-restricted (CR), which were partially shared between patients. The detected CR ncHLAp were immunogenic. Engineered CR ncHLAp-specific TCR-T cells could detect endogenous levels of expression of presented peptides in vitro, and high-avidity TCR-T cells were found to temporarily delay tumor growth in vivo.

ABSTRACT: Translation of the noncoding genome in cancer can generate cryptic (noncanonical) peptides capable of presentation by human leukocyte antigen class I (HLA-I); however, the cancer specificity and immunogenicity of noncanonical HLA-I-bound peptides (ncHLAp) are incompletely understood. Using high-resolution immunopeptidomics, we discovered that cryptic peptides are abundant in the pancreatic cancer immunopeptidome. Approximately 30% of ncHLAp exhibited cancer-restricted translation, and a substantial subset were shared among patients. Cancer-restricted ncHLAp displayed robust immunogenic potential in a sensitive ex vivo T cell priming platform. ncHLAp-reactive, T cell receptor-redirected T cells exhibited tumoricidal activity against patient-derived pancreatic cancer organoids. These findings demonstrate that pancreatic cancer harbors cancer-restricted ncHLAp that can be recognized by cytotoxic T cells. Future therapeutic strategies for pancreatic cancer, and potentially other solid tumors, may include targeting cryptic antigens.

Author Info: (1) Koch Institute at MIT, Cambridge, MA, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. (2) Koch Institute at MIT, Cambridge, MA, USA. Dana

Author Info: (1) Koch Institute at MIT, Cambridge, MA, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. (2) Koch Institute at MIT, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. The Broad Institute of MIT and Harvard, Cambridge, MA, USA. (3) Dana-Farber Cancer Institute, Boston, MA, USA. The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. (4) Dana-Farber Cancer Institute, Boston, MA, USA. The Broad Institute of MIT and Harvard, Cambridge, MA, USA. (5) The Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Dana-Farber Cancer Institute, Boston, MA, USA. (7) The Broad Institute of MIT and Harvard, Cambridge, MA, USA. (8) Dana-Farber Cancer Institute, Boston, MA, USA. The Broad Institute of MIT and Harvard, Cambridge, MA, USA. (9) The Broad Institute of MIT and Harvard, Cambridge, MA, USA. (10) Dana-Farber Cancer Institute, Boston, MA, USA. (11) Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. (12) Dana-Farber Cancer Institute, Boston, MA, USA. (13) Koch Institute at MIT, Cambridge, MA, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. (14) Dana-Farber Cancer Institute, Boston, MA, USA. (15) Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Hale Family Center for Pancreatic Cancer Research at DFCI, Boston, MA, USA. (16) Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. (17) The Broad Institute of MIT and Harvard, Cambridge, MA, USA. (18) Koch Institute at MIT, Cambridge, MA, USA. (19) Koch Institute at MIT, Cambridge, MA, USA. (20) Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Hale Family Center for Pancreatic Cancer Research at DFCI, Boston, MA, USA. (21) Dana-Farber Cancer Institute, Boston, MA, USA. The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Hale Family Center for Pancreatic Cancer Research at DFCI, Boston, MA, USA. (22) Dana-Farber Cancer Institute, Boston, MA, USA. The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. (23) Program in Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA. Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA. Department of Immunology, University of Washington, Seattle, WA, USA. (24) Dana-Farber Cancer Institute, Boston, MA, USA. The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Hale Family Center for Pancreatic Cancer Research at DFCI, Boston, MA, USA. (25) Dana-Farber Cancer Institute, Boston, MA, USA. The Broad Institute of MIT and Harvard, Cambridge, MA, USA. (26) The Broad Institute of MIT and Harvard, Cambridge, MA, USA. (27) Koch Institute at MIT, Cambridge, MA, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. (28) Koch Institute at MIT, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard Medical School, Boston, MA, USA. Hale Family Center for Pancreatic Cancer Research at DFCI, Boston, MA, USA.

Citation: Science 2025 May 8 388:eadk3487 Epub05/08/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40339010

Tags:

Immunotherapy-related cognitive impairment after CAR T cell therapy in mice Spotlight 

(1) Geraghty AC (2) Acosta-Alvarez L (3) Rotiroti MC (4) Dutton S (5) O'Dea MR (6) Kim W (7) Trivedi V (8) Mancusi R (9) Shamardani K (10) Malacon K (11) Woo PJ (12) Martinez-Velez N (13) Pham T (14) Reche-Ley NN (15) Otubu G (16) Castenada EH (17) Nwangwu K (18) Xu H (19) Mulinyawe SB (20) Zamler DB (21) Ni L (22) Cross K (23) Rustenhoven J (24) Kipnis J (25) Liddelow SA (26) Mackall CL (27) Majzner RG (28) Monje M

Cell

Geraghty and Acosta-Alvarez et al. investigated mechanisms underlying impaired cognition following CAR T cell therapy for CNS and non-CNS tumors. In several mouse models, CAR T cells induced neuroinflammation with white matter microglial reactivity, increases in levels of CSF cytokines and chemokines, and dysregulation of oligodendroglial cells and hippocampal neurogenesis. RNAseq analysis of frontal lobes from CAR T cell-treated patients with brain stem tumors confirmed microglial and oligodendrocyte reactivity. In mice, transient depletion of microglia or CCR3 blockade rescued oligodendroglial deficits and improved cognitive performance.

Contributed by Katherine Turner

(1) Geraghty AC (2) Acosta-Alvarez L (3) Rotiroti MC (4) Dutton S (5) O'Dea MR (6) Kim W (7) Trivedi V (8) Mancusi R (9) Shamardani K (10) Malacon K (11) Woo PJ (12) Martinez-Velez N (13) Pham T (14) Reche-Ley NN (15) Otubu G (16) Castenada EH (17) Nwangwu K (18) Xu H (19) Mulinyawe SB (20) Zamler DB (21) Ni L (22) Cross K (23) Rustenhoven J (24) Kipnis J (25) Liddelow SA (26) Mackall CL (27) Majzner RG (28) Monje M

Cell

Geraghty and Acosta-Alvarez et al. investigated mechanisms underlying impaired cognition following CAR T cell therapy for CNS and non-CNS tumors. In several mouse models, CAR T cells induced neuroinflammation with white matter microglial reactivity, increases in levels of CSF cytokines and chemokines, and dysregulation of oligodendroglial cells and hippocampal neurogenesis. RNAseq analysis of frontal lobes from CAR T cell-treated patients with brain stem tumors confirmed microglial and oligodendrocyte reactivity. In mice, transient depletion of microglia or CCR3 blockade rescued oligodendroglial deficits and improved cognitive performance.

Contributed by Katherine Turner

ABSTRACT: Immunotherapies have revolutionized cancer care for many tumor types, but their potential long-term cognitive impacts are incompletely understood. Here, we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis were disrupted. Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes following treatment. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy. Taken together, these findings illustrate targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.

Author Info: (1) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.

Author Info: (1) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. (2) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (3) Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA. (4) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (5) Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10016, USA. (6) Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA. (7) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (8) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (9) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (10) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (11) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (12) Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA. (13) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (14) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (15) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (16) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (17) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (18) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (19) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (20) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (21) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (22) Brain immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130, USA. (23) Brain immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130, USA. (24) Brain immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130, USA. (25) Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY 10016, USA; Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY 10016, USA. (26) Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA; Center for Cancer Cellular Therapy, Stanford School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. (27) Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA; Center for Cancer Cellular Therapy, Stanford School of Medicine, Stanford, CA 94305, USA. (28) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA; Center for Cancer Cellular Therapy, Stanford School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: mmonje@stanford.edu.

Citation: Cell 2025 May 7 Epub05/07/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40359942

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Spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors reveals TIM-3 as a putative target for precancer interception Spotlight 

(1) Zhu B (2) Chen P (3) Aminu M (4) Li JR (5) Fujimoto J (6) Tian Y (7) Hong L (8) Chen H (9) Hu X (10) Li C (11) Vokes N (12) Moreira AL (13) Gibbons DL (14) Solis Soto LM (15) Parra Cuentas ER (16) Shi O (17) Diao S (18) Ye J (19) Rojas FR (20) Vilar E (21) Maitra A (22) Chen K (23) Navin N (24) Nilsson M (25) Huang B (26) Heeke S (27) Zhang J (28) Haymaker CL (29) Velcheti V (30) Sterman DH (31) Kochat V (32) Padron WI (33) Alexandrov LB (34) Wei Z (35) Le X (36) Wang L (37) Fukuoka J (38) Lee JJ (39) Wistuba II (40) Pass HI (41) Davis M (42) Hanash S (43) Cheng C (44) Dubinett S (45) Spira A (46) Rai K (47) Lippman SM (48) Futreal PA (49) Heymach JV (50) Reuben A (51) Wu J (52) Zhang J

Cancer cell

Zhu et al. demonstrated a coordinated interplay between innate and adaptive immunity during the initiation and progression of LUAD pre-cancers, revealing stage-specific remodeling of the tumor microenvironment, including shifts in macrophage polarization and T lymphocyte differentiation. TIM-3 expression increased at early phases of carcinogenesis in human LUAD and in 5 genetically distinct LUAD mouse models. Anti-TIM-3 treatment shifted M1/M2 macrophage polarization, enhanced antigen presentation by DCs, increased T cell activation and cytotoxicity, and decreased tumor burden at pre-cancer, but not advanced cancer stages.

Contributed by Shishir Pant

(1) Zhu B (2) Chen P (3) Aminu M (4) Li JR (5) Fujimoto J (6) Tian Y (7) Hong L (8) Chen H (9) Hu X (10) Li C (11) Vokes N (12) Moreira AL (13) Gibbons DL (14) Solis Soto LM (15) Parra Cuentas ER (16) Shi O (17) Diao S (18) Ye J (19) Rojas FR (20) Vilar E (21) Maitra A (22) Chen K (23) Navin N (24) Nilsson M (25) Huang B (26) Heeke S (27) Zhang J (28) Haymaker CL (29) Velcheti V (30) Sterman DH (31) Kochat V (32) Padron WI (33) Alexandrov LB (34) Wei Z (35) Le X (36) Wang L (37) Fukuoka J (38) Lee JJ (39) Wistuba II (40) Pass HI (41) Davis M (42) Hanash S (43) Cheng C (44) Dubinett S (45) Spira A (46) Rai K (47) Lippman SM (48) Futreal PA (49) Heymach JV (50) Reuben A (51) Wu J (52) Zhang J

Cancer cell

Zhu et al. demonstrated a coordinated interplay between innate and adaptive immunity during the initiation and progression of LUAD pre-cancers, revealing stage-specific remodeling of the tumor microenvironment, including shifts in macrophage polarization and T lymphocyte differentiation. TIM-3 expression increased at early phases of carcinogenesis in human LUAD and in 5 genetically distinct LUAD mouse models. Anti-TIM-3 treatment shifted M1/M2 macrophage polarization, enhanced antigen presentation by DCs, increased T cell activation and cytotoxicity, and decreased tumor burden at pre-cancer, but not advanced cancer stages.

Contributed by Shishir Pant

ABSTRACT: How tumor microenvironment shapes lung adenocarcinoma (LUAD) precancer evolution remains poorly understood. Spatial immune profiling of 114 human LUAD and LUAD precursors reveals a progressive increase of adaptive response and a relative decrease of innate immune response as LUAD precursors progress. The immune evasion features align the immune response patterns at various stages. TIM-3-high features are enriched in LUAD precancers, which decrease in later stages. Furthermore, single-cell RNA sequencing (scRNA-seq) and spatial immune and transcriptomics profiling of LUAD and LUAD precursor specimens from 5 mouse models validate high TIM-3 features in LUAD precancers. In vivo TIM-3 blockade at precancer stage, but not at advanced cancer stage, decreases tumor burden. Anti-TIM-3 treatment is associated with enhanced antigen presentation, T cell activation, and increased M1/M2 macrophage ratio. These results highlight the coordination of innate and adaptive immune response/evasion during LUAD precancer evolution and suggest TIM-3 as a potential target for LUAD precancer interception.

Author Info: (1) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Te

Author Info: (1) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Institute for Data Science in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Medicine, Baylor College of Medicine, Houston, TX, USA. (5) Clinical Research Center in Hiroshima, Hiroshima University Hospital, Hiroshima, Japan. (6) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (12) Department of Pathology, NYU Langone Health, New York, NY, USA. (13) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (15) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (18) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (21) Department of Translational Molecular Pathology and Sheikn Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (23) Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (24) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (25) Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (27) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (28) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (29) Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA. (30) Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA; Cardiothoracic Surgery, NYU Grossman School of Medicine, New York, NY, USA. (31) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (32) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (33) Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, USA. (34) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (35) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (36) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (37) Department of Pathology Informatics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. (38) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (39) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (40) Department of Cardiothoracic Surgery, NYU Langone Health, New York, NY, USA. (41) Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA. (42) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, CA, USA. (43) Department of Medicine, Baylor College of Medicine, Houston, TX, USA. (44) Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA. (45) Pathology & Laboratory Medicine, and Bioinformatics, Boston University, Boston, MA, USA. (46) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (47) UC San Diego School of Medicine, La Jolla, CA, USA. (48) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (49) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (50) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (51) Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (52) Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jzhang20@mdanderson.org.

Citation: Cancer Cell 2025 May 8 Epub05/08/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40345189

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