Cancer immunology research最新文献

{"title":"Anti-CTLA4 Therapy Leads to Early Expansion of a Peripheral Th17 Population and Induction of Th1 Cytokines.","authors":"Mari Nakazawa, Soren Charmsaz, Elsa Hallab, Mike Fang, Chester Kao, Madelena Brancati, Kabeer Munjal, Howard L Li, James M Leatherman, Ervin Griffin, Christopher J Thoburn, Evan J Lipson, Yasser Ged, Jean Hoffman-Censits, Marina Baretti, Laura Tang, Sanjay Bansal, Rachel Garonce-Hediger, Aditi Guha, G Scott Chandler, Rajat Mohindra, Elizabeth M Jaffee, Won Jin Ho, Mark Yarchoan","doi":"10.1158/2326-6066.CIR-24-1055","DOIUrl":"10.1158/2326-6066.CIR-24-1055","url":null,"abstract":"<p><p>The systemic immunologic effects of combining anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) therapy with PDL1 blockade remain incompletely characterized despite the widespread use of this combination in treating various solid tumors across multiple stages of disease. In this study, we investigated the additive impact of anti-CTLA4 on peripheral immune signatures in patients undergoing PDL1 blockade, using blood samples from a cohort of patients receiving checkpoint inhibitor therapy for advanced solid tumors. We performed in-parallel analysis of peripheral blood mononuclear cells using cytometry by time of flight and plasma cytokines using Luminex immunoassay. Our study cohort included 104 patients: 54 received anti-PDL1 alone and 50 received anti-PDL1 in combination with anti-CTLA4. As compared with single-agent anti-PDL1, combination therapy was associated with a greater expansion of CD4+ Th cell subsets, including Th17 (adjusted P = 0.04) and regulatory T cells (adjusted P = 0.02), after multivariable and multiple testing adjustment. In patients receiving anti-CTLA4, examination of functional marker expression within the Th17 subset revealed an increase in the expression of the Th1-related transcription factor TBET (P = 0.003). Assessment of the peripheral cytokine signatures showed an increase in Th1-associated cytokines (P = 0.002) in recipients of combination anti-PDL1 and anti-CTLA4, particularly the IFNγ-inducible cytokines MIG (adjusted P = 0.05) and IP-10 (adjusted P = 0.05). Our results confirm prior reports that anti-CTLA4 therapy is associated with the augmentation of Th17 cell subsets, and they also show that anti-CTLA4 may reshape CD4+ T-cell responses through Th17-to-Th1 plasticity, revealing a potential mechanism for enhanced antitumor immunity with broader implications for immune modulation in immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"836-846"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12136996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAR Binders Affect CAR T-cell Tonic Signaling, Durability, and Sensitivity to Target.","authors":"Divanshu Shukla, Khatuna Gabunia, Shannon E McGettigan, Prachi R Patel, Shannon Christensen, Ting-Jia Fan, Decheng Song, Yanping Luo, Yanling Wang, Huaishan Wang, Regina M Young, Carl H June, John Scholler, James L Riley","doi":"10.1158/2326-6066.CIR-24-1347","DOIUrl":"10.1158/2326-6066.CIR-24-1347","url":null,"abstract":"<p><p>Patients can develop human anti-mouse immune responses against CD19-specific chimeric antigen receptor (CAR) T cells due to the use of a murine CD19-specific single-chain variable fragment to redirect T cells. We screened a yeast display library to identify an array of fully human CD19 single-chain variable fragment binders and performed a series of studies to select the most promising fully human CAR. We observed significant differences in the ability of CARs employing these CD19 binders to be expressed on the cell surface, induce tonic signaling, redirect T-cell function, mediate tumor killing, recognize lower levels of CD19 antigen, and maintain function upon continuous antigen exposure. From this initial analysis, CAR T cells using two binders (42 and 52) were selected for additional studies. Although CAR T cells using both binders controlled tumor growth well in vivo, we advanced a CAR construct using binder 42 for more advanced preclinical testing because of its greater similarity to binders based on the antibody FMC63, which is the murine antibody underlying four FDA-approved CD19-specific CAR T-cell therapies, and ability to robustly respond to tumors expressing lower levels of CD19. We found that this binder uniquely bound CD19 using distinct contact residues than FMC63 and with ∼40-fold lower affinity. CARs using binder 42 were non-inferior to those using the FMC63 binder in a mouse model of acute lymphoblastic leukemia, indicating that CAR T cells using binder 42 should be considered for clinical use.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"867-880"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Memory-like Natural Killer Cell and CD19 Antibody-Based Immunotherapy in Combination with Tyrosine Kinase Inhibition Has Antitumor Effects against Ph(-like) Acute Lymphoblastic Leukemia.","authors":"Zoya Eskandarian, Richard Hauch, Sabrina Schuster, Dorothee Winterberg, Hjördis Grabellus, Carlotta Imelmann, Anna-Lena Heitmann, Marlene Goos, Khadija Rudloff, Julia Strauss, Gerrit Wolters-Eisfeld, Peter Nollau, Katja Klausz, Ulrich Schüller, Matthias Peipp, Michael Spohn, Martin A Horstmann","doi":"10.1158/2326-6066.CIR-24-0746","DOIUrl":"10.1158/2326-6066.CIR-24-0746","url":null,"abstract":"<p><p>Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a molecularly distinct tyrosine kinase-driven cancer that has a high relapse rate and poor response toward combinatorial chemotherapy. Tyrosine kinase inhibitors (TKI) in the clinic improve the survival of patients with Ph-like ALL. Engineered antibody and cell-based immunotherapies can advance treatment for this genetic subtype of ALL. Allogeneic memory-like natural killer (ML-NK) cells have been used to treat leukemia and have shown a low risk of graft-versus-host reaction, which may be combined with leukemia epitope-targeting antibodies. However, mutation or pathway-directed TKI of Ph-like ALL can interfere with memory function and antibody-dependent NK cell-mediated cytotoxicity (ADCC). In this study, we explored the potential of ML-NK cells and Fc-enhanced CD19-ADCC in combination with TKI directed against kinase-driven leukemia models, including patient-derived xenografted Ph-like ALL. We demonstrate that receptor cross-linking in coculture with K562 feeder cells generated a more robust memory-like state of NK cells than coactivation with soluble IL-12, IL-15, and IL-18, as determined by genomic and functional studies. After receptor cross-linking and subsequent ILs preactivation, the optimized ML-NK cells showed enhanced antileukemic effector functions, which could compensate for exhausted B-cell precursor leukemia-infiltrating primary NK cells. TKI differentially affected multiple features of NK cell biology including viability, expansion, metabolism, receptor repertoire, and cytotoxicity. ADCC was maintained upon exposure to specific Abelson (ABL) or Janus kinase (JAK) inhibitors, in contrast to the multitarget TKI dasatinib impeding spleen tyrosine kinase-dependent ADCC. In conclusion, optimized ML-NK cell and CD19 antibody-based immunotherapy combined with carefully selected TKI demonstrates significant in vitro treatment efficacy in kinase-driven leukemia.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"881-896"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal Stem Cells and Fibroblasts Contribute to Microvascular Proliferation in Glioblastoma and are Correlated with Immunosuppression and Poor Outcome.","authors":"Candice C Poon, Shelley M Herbrich, Yulong Chen, Anwar Hossain, Gregory N Fuller, Sonali Jindal, Sreyashi Basu, Daniel Ledbetter, Marc Macaluso, Lynnette M Phillips, Joy Gumin, Zhong He, Brittany C Parker Kerrigan, Sanjay K Singh, Pratishtha Singh, Mohammed Fayyad Zaman, Derek Ng Tang, Sangeeta Goswami, Frederick F Lang, Padmanee Sharma","doi":"10.1158/2326-6066.CIR-24-0743","DOIUrl":"10.1158/2326-6066.CIR-24-0743","url":null,"abstract":"<p><p>Microvascular proliferation (MVP) is a disease-defining hallmark of glioblastoma and other World Health Organization grade 4 gliomas. MVP also serves as a poor prognostic marker in various solid tumors. Despite its clinical significance, the mechanisms and biological consequences of MVP are controversial and remain unclear. In this study, we performed single-cell RNA sequencing on paired CD45-CD105+ vascular/perivascular stromal cells (PVSC) and CD45+CD105± immune cells from 16 primary glioma patient samples, both with and without MVP. This analysis revealed the presence of developmentally related mesenchymal stem cells alongside cancer-associated fibroblasts, pericytes, fibromyocytes, and smooth muscle cells within the CD45-CD105+ compartment. RNA velocity analysis identified PDGFRB as a putative driver gene guiding mesenchymal stem cells toward more mature PVSCs in the context of MVP. Signaling network analysis and digital spatial profiling uncovered interactions between PDGFRB+ PVSCs and immunosuppressive myeloid cell subsets enriched in the perivascular niche, suggesting targetable receptor-ligand interactions. Additionally, a gene signature of MVP-associated PVSCs from gliomas predicted worse prognosis in multiple other solid tumors. This study provides a transcriptomic cell atlas of PVSCs and immune cells in glioma, helping to refine the biological model of MVP which has traditionally focused on endothelial cells.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"804-820"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytotoxic Chemotherapy in a 3D Microfluidic Device Induces Dendritic Cell Recruitment and Trogocytosis of Cancer Cells.","authors":"Dohyun Park, Inae Park, Bohwa Han, Yujin Baek, Dowon Moon, Noo Li Jeon, Junsang Doh","doi":"10.1158/2326-6066.CIR-24-0263","DOIUrl":"10.1158/2326-6066.CIR-24-0263","url":null,"abstract":"<p><p>Cytotoxic chemotherapy that kills cancer cells can also elicit antitumor immune responses. Therefore, understanding the immunogenic context of cytotoxic chemotherapy can improve combination immunotherapies. In this study, we sought to improve our understanding of dendritic cell (DC) dynamics in cytotoxic chemotherapy-treated tumor tissues by developing three-dimensional (3D) microfluidic devices that enable high-resolution visualization of cellular dynamics. Specifically, microfluidic chips mimicking 3D tumor tissues were fabricated and used. Collagen gel blocks encapsulating cancer cells in microfluidics were treated with various concentrations of oxaliplatin (OXP; 0-40 μg/mL). Then, DCs were attached on the side of the collagen gel blocks, and migration of DCs within the 3D gels was quantitatively analyzed. Interactions between OXP-treated cancer cells and DCs were observed by high-resolution time-lapse imaging. Active infiltration of DCs was predominantly observed when OXP was administrated, indicating OXP-treated cancer cells release factors promoting DC motility. The highest frequency of DC recruitment was detected at a moderate OXP concentration, suggesting that optimizing the dosage of cytotoxic chemotherapy is crucial in order to improve immunogenic cell death. High-resolution video microscopy revealed that DCs employ trogocytosis to disassemble dying/dead cancer cells and acquire antigens, as opposed to phagocytosing the entire cancer cells. Microfluidic chip-based observations may provide new insights for the design of new therapeutic strategies to combine chemotherapy and immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"931-938"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors.","authors":"","doi":"10.1158/2326-6066.CIR-13-6-WWR","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-13-6-WWR","url":null,"abstract":"","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":"13 6","pages":"791"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eph Receptors Activate Myeloid Checkpoint Receptor LILRB5 to Support Tumor Development.","authors":"Yubo He, Chengcheng Zhang, Lingxiao Tan, Mi Deng, Xiaoye Liu, Ryan Huang, Xing Yang, Jingjing Xie, Qi Lou, Meng Fang, Caroline Smith, Samuel John, Wei Xiong, Xin Li, Cheryl Lewis, Jade Homsi, Ankit Gupta, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang","doi":"10.1158/2326-6066.CIR-24-0737","DOIUrl":"10.1158/2326-6066.CIR-24-0737","url":null,"abstract":"<p><p>Immunosuppressive myeloid cells are critical obstacles to T cell-centered immune checkpoint blockade therapies, which have been successful in treating a fraction of patients with cancer. How tumor cells interact with myeloid cells to regulate immune responses and tumor development is unclear. In this study, we report that certain membrane tyrosine kinase Eph receptors, including EphA7 and EphB1, specifically bind the immune inhibitory receptors leukocyte Ig-like receptor family B 5 (LILRB5) and LILRB2. These Eph receptors induce LILRB5-mediated signaling activation, and LILRB5 also activates Eph receptor signaling. Activation of LILRB5 promoted immunosuppressive marker expression and inhibited activating marker expression on myeloid cells from patients with cancer in vitro. Upon myeloid cell-specific expression of LILRB5 in transgenic mice, the interaction between the Eph receptor on tumor cells and LILRB5 on myeloid cells led to increased tumor growth, increased immunosuppressive myeloid cells, and decreased frequencies of functional T cells compared with control mice. Eph-induced LILRB5 signaling and functions were reversed by LILRB5 blockade. In sum, certain Eph receptors functionally interact with the myeloid checkpoint receptor LILRB5 resulting in bidirectional signaling, and LILRB5 plays an important role in supporting immunosuppressive myeloid cells and sustaining tumor development.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"821-835"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CTG-initiated cryptic peptide translation up and downstream of a canonical ATG start codon is enhanced by TLR stimulation and induces tumor regression in mice.","authors":"Ziye Song, Youkyung Lim, Anneloes van Krimpen, Mitchell A A Geleijnse, Manon Messchendorp, Jane S A Voerman, Ling Li, Emma G M Tondeur, Gunja Mishra, Brett J Hos, Dwin G B Grashof, Ralph Stadhouders, Harmen J G van de Werken, Peter D Katsikis, Christopher Schliehe","doi":"10.1158/2326-6066.CIR-24-0467","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0467","url":null,"abstract":"<p><p>Cytotoxic T-lymphocytes (CTLs) screen cells for signs of infection and transformation by recognizing peptides displayed on major histocompatibility complex (MHC) class I molecules. Next to canonical ATG-initiated open reading frames (ORFs), non-canonical translation can result in synthesis of non-conventional or `cryptic´ polypeptides. These can originate from translation initiation at non-canonical start codons, a process previously associated with inflammation and oncogenic transformation. Cryptic translation products are efficiently presented on MHC class I molecules and therefore increasingly recognized as potential targets for cancer immunotherapy. Here, we studied how localization of a CTG-initiated ORF relative to a canonical ATG start codon can influence cryptic expression after innate immune stimulation. We generated immortalized C57BL/6J mouse-derived bone marrow progenitor cells (HoxB8) expressing tandem minigene constructs, which encoded a CTG-driven chicken ovalbumin-derived SIINFEKL (S8L) epitope (CTG-S8L; H-2Kb-restriced) either up or downstream of a canonical ATG-initiated UTY-derived peptide WI9 (ATG-WI9; H-2Db-restriced). Treatment of HoxB8-derived macrophages with Toll-like receptor agonists enhanced position-independent CTG-S8L translation, without affecting ATG-driven expression. Downstream CTG-S8L translation was driven by leaky scanning or ribosome re-initiation rather than read-through translation. Mouse AE17 mesothelioma and B16F10 melanoma cells expressing cryptic S8L either up or downstream of a canonical ORF were efficiently killed by H-2Kb/S8L-restriced OT-I T-cells in vitro, even though their antigen expression levels were extremely low. Mice implanted with tumors expressing cryptic S8L showed delayed tumor progression in vivo. In summary, our study contributes to the characterization of non-canonical start codon-driven cryptic antigen translation and highlights its potential for cancer immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell analysis of post-translational modifications identifies immunosuppressive macrophage subtypes in the HBV-positive hepatocellular carcinoma microenvironment.","authors":"Huakan Zhao, Ran Ren, Xi Zhang, Mengtao Zhan, Jinwei Cui, Jun Zhang, Xi Liu, Lei Wu, Yu Chen, Yu Zhou, Yang Xiao, Jiangang Zhang, Yang Chen, Lu Zheng, Bing Sun, Yongsheng Li","doi":"10.1158/2326-6066.CIR-24-1298","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1298","url":null,"abstract":"<p><p>Analysis of post-translational modifications (PTMs) of proteins can provide new insight, beyond that obtained from analysis of protein levels, for understanding the tumor microenvironment (TME). The characteristics of PTMs in immune cells, along with their spatial distribution, have not been comprehensively integrated, which impedes our understanding of the complexity and heterogeneity of the TME in hepatocellular carcinoma (HCC). Herein, we used a strategy that combines antibodies for specific PTMs with mass cytometry and mass spectrometry technologies to identify PTMs at single-cell resolution. We found that the phosphorylation status of M2 macrophages was substantially altered in tumor tissues from patients with hepatitis B virus (HBV)-positive HCC. Utilizing the expression profiles of site-specific phospho-HSP27, STAT1, and TRIM28, we classified M2 macrophages into four distinct subtypes: M2-P0 (absence of any of the three phospho-proteins), M2-P1 (presence of one of the three phospho-proteins), M2-P2 (presence of two of the three phospho-proteins), and M2-P3 (presence of all three phospho-proteins). The spatial relationships and functional characteristics of these M2 macrophage subpopulations were assessed using single-cell PTM (scPTM) omics. The abundance of the M2-P2 and M2-P3 subtypes was closely associated with an immunosuppressive TME and responsiveness to immunotherapy in HBV+ HCC. Overall, this study introduces a scPTM omics approach that uncovers subtypes of macrophages associated with immunotherapeutic responses in HBV+ HCC and provides valuable insights into the immunosuppressive TME of HCC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Secretion of a VEGF-blocking scFv enhances CAR T-cell potency.","authors":"Valentina M Supper, Hannah Donner, Filippo Birocchi, Alexandra Bratt, Giulia Escobar, Michael C Kann, Sangwoo Park, Grace Martin, Felix Korell, Hana Takei, Alexander Armstrong, Aiyana Parker, Diego Salas-Benito, Eli P Darnell, Stefanie R Bailey, Tamina Kienka, Merle Philips, Amanda Bouffard, Sadie Goncalves, Bryan D Choi, Nicholas J Haradhvala, Marcela V Maus, Mark B Leick","doi":"10.1158/2326-6066.CIR-24-0876","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0876","url":null,"abstract":"<p><p>CAR T-cell therapy is an effective treatment strategy in B-cell malignancies, however, its efficacy in solid tumors remains limited. VEGF-targeted drugs are used as antitumor agents to target abnormal tumor vasculature, however, toxicities associated with systemic VEGF blockade limit their maximal therapeutic benefit. Increasing evidence suggests a role for VEGF in the immunosuppressive tumor microenvironment (TME), including through direct induction of T cell-effector dysfunction. Herein, we show that CAR T cells from patients treated with FDA-approved CAR T-cell products express members of the VEGF signaling pathway and this expression is correlated with patient non-response. To overcome putative VEGF-induced CAR T-cell dysfunction and deliver local VEGF blockade, we generated CAR T cells that secrete a VEGF-targeting scFv to block T-cell and tumor-derived VEGF within the TME. These CAR T cells potently inhibited VEGF signaling and angiogenesis in vitro, and exhibited enhanced activation, cytotoxicity, proliferation, and effector function across different antigen and solid tumor contexts. VEGF scFv-secreting CAR T cells showed improved tumor control in immunocompromised murine metastatic and orthotopic models of ovarian and lung cancer. These findings suggest that CAR T cell-secreted VEGF blockade augments CAR T-cell performance, inhibits VEGF without systemic toxicity, and warrants further development.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}