Journal Articles

Durable response to CAR T is associated with elevated activation and clonotypic expansion of the cytotoxic native T cell repertoire Spotlight 

(1) Cheloni G (2) Karagkouni D (3) Pita-Juarez Y (4) Torres D (5) Kanata E (6) Liegel J (7) Avigan Z (8) Saldarriaga I (9) Chedid G (10) Rallis K (11) Miles B (12) Tiwari G (13) Kim J (14) Mattie M (15) Rosenblatt J (16) Vlachos IS (17) Avigan D

Nature communications | Free PMC Article

Cheloni and Karagkouni et al. characterized endogenous (non-CAR) T cells in patients with LBCL treated with anti-CD19 CAR T cells, who experienced either long-term response (LtR) or relapse (R). T cells from LtR patients (cf. R patients) were less differentiated at leukapheresis, had higher expression of cytotoxic and pro-inflammatory genes (which increased after CAR T infusion), and showed expansion of cytotoxic TCR clonotypes. R patient T cells, NK cells, and monocytes expressed genes associated with immune regulation and dampened responses. Clonotypic T cell expansion 4 weeks after CAR T treatment predicted patient response better than CAR T peak expansion.

Contributed by Alex Najibi

(1) Cheloni G (2) Karagkouni D (3) Pita-Juarez Y (4) Torres D (5) Kanata E (6) Liegel J (7) Avigan Z (8) Saldarriaga I (9) Chedid G (10) Rallis K (11) Miles B (12) Tiwari G (13) Kim J (14) Mattie M (15) Rosenblatt J (16) Vlachos IS (17) Avigan D

Nature communications | Free PMC Article

Cheloni and Karagkouni et al. characterized endogenous (non-CAR) T cells in patients with LBCL treated with anti-CD19 CAR T cells, who experienced either long-term response (LtR) or relapse (R). T cells from LtR patients (cf. R patients) were less differentiated at leukapheresis, had higher expression of cytotoxic and pro-inflammatory genes (which increased after CAR T infusion), and showed expansion of cytotoxic TCR clonotypes. R patient T cells, NK cells, and monocytes expressed genes associated with immune regulation and dampened responses. Clonotypic T cell expansion 4 weeks after CAR T treatment predicted patient response better than CAR T peak expansion.

Contributed by Alex Najibi

ABSTRACT: While Chimeric Antigen Receptor (CAR) T cell therapy may result in durable remissions in recurrent large B cell lymphoma, persistence is limited and the mechanisms underlying long-term response are not fully elucidated. Using longitudinal single-cell immunoprofiling, here we compare the immune landscape in durable remission versus early relapse patients following CD19 CAR T cell infusion in the NCT02348216 (ZUMA-1) trial. Four weeks post-infusion, both cohorts demonstrate low circulating CAR T cells. We observe that long-term remission is associated with elevated native cytotoxic and proinflammatory effector cells, and post-infusion clonotypic expansion of effector memory T cells. Conversely, early relapse is associated with impaired NK cell cytotoxicity and elevated immunoregulatory cells, potentially dampening native T cell activation. Thus, we suggest that durable remission to CAR T is associated with a distinct T cell signature and pattern of clonotypic expansion within the native T cell compartment post-therapy, consistent with their contribution to the maintenance of response.

Author Info: (1) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Bos

Author Info: (1) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (2) Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (3) Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (4) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. (5) Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. (6) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (7) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. (8) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (9) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (10) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (11) Kite, a Gilead Company, Santa Monica, CA, USA. (12) Kite, a Gilead Company, Santa Monica, CA, USA. (13) Kite, a Gilead Company, Santa Monica, CA, USA. (14) Kite, a Gilead Company, Santa Monica, CA, USA. (15) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (16) Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Spatial Technologies Unit, Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA. (17) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. davigan@bidmc.harvard.edu. Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA. davigan@bidmc.harvard.edu. Harvard Medical School, Boston, MA, USA. davigan@bidmc.harvard.edu.

Citation: Nat Commun 2025 May 23 16:4819 Epub05/23/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40410132

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Blockade of CLEVER-1 restrains immune evasion and enhances anti-PD-1 immunotherapy in gastric cancer Spotlight 

(1) Yu K (2) Cao Y (3) Zhang Z (4) Wang L (5) Gu Y (6) Xu T (7) Zhang X (8) Guo X (9) Shen Z (10) Qin J

Journal for immunotherapy of cancer | Free PMC Article

Yu‍, Cao, Zhang et al. showed that in the gastric cancer TME, Common Lymphatic Endothelial and Vascular Endothelial Receptor-­1 (CLEVER-­1) was primarily expressed on TAMs that increasingly polarized from a proinflammatory to an immunosuppressive profile as disease progressed. CLEVER-1+ TAM abundance was associated with fewer and exhausted tumor-infiltrating CD8+ T cells, poor prognosis, and weak response/resistance to anti-PD-­1-based therapy. In cell cultures, CLEVER-­1 blockade promoted a proinflammatory TAM phenotype and CD8+ T cell cytotoxicity/proliferation, and synergized with PD-­1 blockade to enhance antitumor responses.

Contributed by Paula Hochman

(1) Yu K (2) Cao Y (3) Zhang Z (4) Wang L (5) Gu Y (6) Xu T (7) Zhang X (8) Guo X (9) Shen Z (10) Qin J

Journal for immunotherapy of cancer | Free PMC Article

Yu‍, Cao, Zhang et al. showed that in the gastric cancer TME, Common Lymphatic Endothelial and Vascular Endothelial Receptor-­1 (CLEVER-­1) was primarily expressed on TAMs that increasingly polarized from a proinflammatory to an immunosuppressive profile as disease progressed. CLEVER-1+ TAM abundance was associated with fewer and exhausted tumor-infiltrating CD8+ T cells, poor prognosis, and weak response/resistance to anti-PD-­1-based therapy. In cell cultures, CLEVER-­1 blockade promoted a proinflammatory TAM phenotype and CD8+ T cell cytotoxicity/proliferation, and synergized with PD-­1 blockade to enhance antitumor responses.

Contributed by Paula Hochman

BACKGROUND: Gastric cancer (GC) remains a major global health burden. Despite the advancements in immunotherapy for patients with GC, the heterogeneity of GC limits response rates, especially in immune "cold" subtypes, including genomically stable and epithelial-mesenchymal transition GC. Common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1), a newly recognized immune checkpoint molecule predominantly expressed on tumor-associated macrophages (TAMs), remains poorly understood in GC. This study aims to explore the clinical significance of CLEVER-1(+)TAM infiltration, elucidate its role in modulating the tumor immune landscape, and investigate the therapeutic potential of CLEVER-1 blockade in enhancing immunotherapy. METHODS: This study analyzed two independent GC cohorts and single-cell RNA sequencing data (GSE183904). CLEVER-1 expression in TAMs was assessed via multiplex immunofluorescence, flow cytometry, and RNA sequencing. The clinical relevance of CLEVER-1(+)TAM infiltration was evaluated in relation to tumor, node, metastases staging, molecular subtypes, prognosis, and immunochemotherapy response. Transcriptomic and pathway analyses characterized the immunophenotype of CLEVER-1(+)TAMs. Functional assays examined their suppression on CD8(+)T cells, while interventional experiments assessed the impact of CLEVER-1 blockade alone or with programmed cell death protein-1 (PD-1) inhibition. RESULTS: CLEVER-1 was predominantly expressed on TAMs in GC and was associated with worse clinical outcomes. Transcriptomic and phenotypic analyses revealed that CLEVER-1(+)TAMs display a dynamic immunophenotype and critically suppress T-cell function, fostering an immunosuppressive microenvironment. High CLEVER-1(+)TAM infiltration was linked to poor response or adaptive resistance to PD-1 blockade therapy. CLEVER-1 blockade reprogrammed TAMs toward a pro-inflammatory phenotype, resulting in enhanced CD8(+)T cell cytotoxicity and proliferation. Co-targeting CLEVER-1 and PD-1 synergistically enhanced antitumor responses. CONCLUSIONS: High infiltration of CLEVER-1(+)TAMs indicates immune suppression and poor prognosis in GC. The combination of CLEVER-1 and PD-1 blockade emerges as a dual-pronged strategy to boost immune-mediated tumor control and prevent treatment relapse in GC.

Author Info: (1) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (2) Department

Author Info: (1) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (2) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (3) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (4) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (5) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (6) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. (7) Department of Pathology, Zhongshan Hospital Fudan University, Shanghai, China. (8) Department of Pathology, Zhongshan Hospital Fudan University, Shanghai, China. (9) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China qin.jing@zs-hospital.sh.cn shen.zhenbin@zs-hospital.sh.cn. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (10) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China qin.jing@zs-hospital.sh.cn shen.zhenbin@zs-hospital.sh.cn. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China.

Citation: J Immunother Cancer 2025 May 22 13: Epub05/22/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40404204

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INBRX-106: a hexavalent OX40 agonist that drives superior antitumor responses via optimized receptor clustering Spotlight 

(1) Holay N (2) Yadav R (3) Ahn SJ (4) Kasiewicz MJ (5) Polovina A (6) Rolig AS (7) Staebler T (8) Becklund B (9) Simons ND (10) Koguchi Y (11) Eckelman BP (12) de Durana YD (13) Redmond WL

Journal for immunotherapy of cancer | Free PMC Article

Holay et al. engineered INBRX-106, an OX40 agonist composed of six binding domains fused to a human IgG1 Fc. INBRX-106 promoted distinct OX40 surface clustering and internalization in T cells, improving NFκB signaling and CD8+ T cell-dependent tumor control compared to lower-valency agonists. The therapy enhanced CD8+ T cell proliferation in tdLNs and frequency in tumors, and upregulated cytokine–receptor interaction and cytotoxicity genes. Interestingly, INBRX-106 only modestly reduced Tregs compared to other agonists. In a phase 1/2 trial, INBRX-106 synergized with ICB to enhance peripheral T cell proliferation and activation.

Contributed by Morgan Janes

(1) Holay N (2) Yadav R (3) Ahn SJ (4) Kasiewicz MJ (5) Polovina A (6) Rolig AS (7) Staebler T (8) Becklund B (9) Simons ND (10) Koguchi Y (11) Eckelman BP (12) de Durana YD (13) Redmond WL

Journal for immunotherapy of cancer | Free PMC Article

Holay et al. engineered INBRX-106, an OX40 agonist composed of six binding domains fused to a human IgG1 Fc. INBRX-106 promoted distinct OX40 surface clustering and internalization in T cells, improving NFκB signaling and CD8+ T cell-dependent tumor control compared to lower-valency agonists. The therapy enhanced CD8+ T cell proliferation in tdLNs and frequency in tumors, and upregulated cytokine–receptor interaction and cytotoxicity genes. Interestingly, INBRX-106 only modestly reduced Tregs compared to other agonists. In a phase 1/2 trial, INBRX-106 synergized with ICB to enhance peripheral T cell proliferation and activation.

Contributed by Morgan Janes

BACKGROUND: Immunotherapies targeting immune checkpoint inhibitors have revolutionized cancer treatment but are limited by incomplete patient responses. Costimulatory agonists like OX40 (CD134), a tumor necrosis factor receptor family member critical for T-cell survival and differentiation, have shown preclinical promise but limited clinical success due to suboptimal receptor activation. Conventional bivalent OX40 agonists fail to induce the trimeric engagement required for optimal downstream signaling. To address this, we developed INBRX-106, a hexavalent OX40 agonist designed to enhance receptor clustering independently of Fc-mediated crosslinking and boost antitumor T-cell responses. METHODS: We assessed INBRX-106's effects on receptor clustering, signal transduction, and T-cell activation using NF-k§ reporter assays, confocal microscopy, flow cytometry, and single-cell RNA sequencing. Therapeutic efficacy was evaluated in murine tumor models and ex vivo human samples. Clinical samples from a phase I/II trial (NCT04198766) were also analyzed for immune activation. RESULTS: INBRX-106 demonstrated superior receptor clustering and downstream signaling compared with bivalent agonists, leading to robust T-cell activation and proliferation. In murine models, hexavalent OX40 agonism resulted in significant tumor regression, enhanced survival, and increased CD8(+) T-cell effector function. Clinical pharmacodynamic analysis in blood samples from patients treated with INBRX-106 showed heightened T-cell activation and proliferation, particularly in central and effector memory subsets, validating our preclinical findings. CONCLUSIONS: Our data establish hexavalent INBRX-106 as a differentiated and more potent OX40 agonist, showcasing its ability to overcome the limitations of conventional bivalent therapies by inducing superior receptor clustering and multimeric engagement. This unique clustering mechanism amplifies OX40 signaling, driving robust T-cell activation, proliferation, and effector function in preclinical and clinical settings. These findings highlight the therapeutic potential of INBRX-106 and its capacity to redefine OX40-targeted immunotherapy, providing a compelling rationale for its further clinical development in combination with checkpoint inhibitors.

Author Info: (1) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. (2) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA

Author Info: (1) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. (2) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. Oregon Health and Science University, Portland, Oregon, USA. (3) Inhibrx Biosciences Inc, La Jolla, California, USA. (4) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. (5) Inhibrx Biosciences Inc, La Jolla, California, USA. (6) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. Oregon Health and Science University, Portland, Oregon, USA. (7) Inhibrx Biosciences Inc, La Jolla, California, USA. (8) Inhibrx Biosciences Inc, La Jolla, California, USA. (9) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. (10) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. The Ohio State University, Columbus, Ohio, USA. (11) Inhibrx Biosciences Inc, La Jolla, California, USA. (12) Inhibrx Biosciences Inc, La Jolla, California, USA william.redmond@providence.org yaiza@inhibrx.com. (13) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA william.redmond@providence.org yaiza@inhibrx.com.

Citation: J Immunother Cancer 2025 May 21 13: Epub05/21/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40404202

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Preferential tumor targeting of HER2 by iPSC-derived CAR T cells engineered to overcome multiple barriers to solid tumor efficacy Featured  

(1) Hosking MP (2) Shirinbak S (3) Omilusik K (4) Chandra S (5) Kaneko MK (6) Gentile A (7) Yamamoto S (8) Shrestha B (9) Grant J (10) Boyett M (11) Cardenas D (12) Keegan H (13) Ibitokou S (14) Pavon C (15) Mizoguchi T (16) Ihara T (17) Nakayama D (18) Abujarour R (19) Lee TT (20) Clarke R (21) Goodridge J (22) Peralta E (23) Maeda T (24) Takagi J (25) Arimori T (26) Kato Y (27) Valamehr B

Cell stem cell

Hosking et al. developed an allogeneic, off-the-shelf CAR T cell product derived from iPSCs, which allowed for extensive genetic engineering and uniform expression of transgenes, including a HER2-targeting CAR (to detect wild-type, truncated, and misfolded HER2), TGFβR2–IL-18R fusion (to resist TGFβ-mediated immunosuppression), CXCR2 (to enhance trafficking to tumors), IL-7–IL-7R fusion (to enhance metabolism and persistence) and hnCD16 (to enhance antitumor efficacy through ADCC and target multiple antigens when combined antigen-targeting antibodies). The resulting H2-7E iT cell product selectively targeted and killed HER2+ cancer cells (without harming HER2+ healthy cells) both in vitro and in vivo.

(1) Hosking MP (2) Shirinbak S (3) Omilusik K (4) Chandra S (5) Kaneko MK (6) Gentile A (7) Yamamoto S (8) Shrestha B (9) Grant J (10) Boyett M (11) Cardenas D (12) Keegan H (13) Ibitokou S (14) Pavon C (15) Mizoguchi T (16) Ihara T (17) Nakayama D (18) Abujarour R (19) Lee TT (20) Clarke R (21) Goodridge J (22) Peralta E (23) Maeda T (24) Takagi J (25) Arimori T (26) Kato Y (27) Valamehr B

Cell stem cell

Hosking et al. developed an allogeneic, off-the-shelf CAR T cell product derived from iPSCs, which allowed for extensive genetic engineering and uniform expression of transgenes, including a HER2-targeting CAR (to detect wild-type, truncated, and misfolded HER2), TGFβR2–IL-18R fusion (to resist TGFβ-mediated immunosuppression), CXCR2 (to enhance trafficking to tumors), IL-7–IL-7R fusion (to enhance metabolism and persistence) and hnCD16 (to enhance antitumor efficacy through ADCC and target multiple antigens when combined antigen-targeting antibodies). The resulting H2-7E iT cell product selectively targeted and killed HER2+ cancer cells (without harming HER2+ healthy cells) both in vitro and in vivo.

Chimeric antigen receptor (CAR) T cell therapies in solid tumors have been limited by on-target, off-tumor toxicity, antigen heterogeneity, and an inability to simultaneously overcome multiple diverse resistance mechanisms within the tumor microenvironment that attenuate anti-tumor activity. Here, we describe an induced pluripotent stem cell (iPSC)-derived CAR T cell that combines a human epidermal growth factor receptor 2 (HER2)-targeting CAR-differentially recognizing tumor from normal cells and enabling detection of both truncated and misfolded HER2-with multiplex editing designed to address and overcome obstacles to maximize efficacy in solid tumor indications. The iPSC-derived, HER2-directed CAR T cells maintained potent HER2-specific anti-tumor activity in both in vitro and in vivo settings, with limited cytolytic targeting of HER2+ normal targets. Combination with therapeutic antibodies enabled comprehensive multi-antigen targeting through both the CAR and a high-affinity, non-cleavable CD16a Fc receptor. Additionally, specific engineering of interleukin (IL)-7R-fusion, transforming growth factor _ (TGF-_)-IL-18R, and CXCR2 enabled sustained persistence, resistance to TGF-_-mediated suppression, and specific migration to the tumor.

Author Info: (1) Fate Therapeutics, Inc., San Diego, CA, USA. Electronic address: martin.hosking@fatetherapeutics.com. (2) Fate Therapeutics, Inc., San Diego, CA, USA. (3) Fate Therapeutics, In

Author Info: (1) Fate Therapeutics, Inc., San Diego, CA, USA. Electronic address: martin.hosking@fatetherapeutics.com. (2) Fate Therapeutics, Inc., San Diego, CA, USA. (3) Fate Therapeutics, Inc., San Diego, CA, USA. (4) Fate Therapeutics, Inc., San Diego, CA, USA. (5) Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan. (6) Fate Therapeutics, Inc., San Diego, CA, USA. (7) Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan. (8) Fate Therapeutics, Inc., San Diego, CA, USA. (9) Fate Therapeutics, Inc., San Diego, CA, USA. (10) Fate Therapeutics, Inc., San Diego, CA, USA. (11) Fate Therapeutics, Inc., San Diego, CA, USA. (12) Fate Therapeutics, Inc., San Diego, CA, USA. (13) Fate Therapeutics, Inc., San Diego, CA, USA. (14) Fate Therapeutics, Inc., San Diego, CA, USA. (15) Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan. (16) Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan. (17) Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan. (18) Fate Therapeutics, Inc., San Diego, CA, USA. (19) Fate Therapeutics, Inc., San Diego, CA, USA. (20) Fate Therapeutics, Inc., San Diego, CA, USA. (21) Fate Therapeutics, Inc., San Diego, CA, USA. (22) Fate Therapeutics, Inc., San Diego, CA, USA. (23) Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan. (24) Institute for Protein Research, Osaka University, 3-2, Yamadaoka, Suita 565-0871, Osaka, Japan. (25) Institute for Protein Research, Osaka University, 3-2, Yamadaoka, Suita 565-0871, Osaka, Japan. (26) Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan. (27) Fate Therapeutics, Inc., San Diego, CA, USA. Electronic address: bob.valamehr@fatetherapeutics.com.

Citation: Cell Stem Cell 2025 May 30 Epub05/30/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40472844

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

Spotlight 

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

Spotlight 

(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

Spotlight 

(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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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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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

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