Cancer immunology research最新文献

{"title":"IGM-7354, an Immunocytokine with IL15 Fused to an Anti-PD-L1 IgM, Induces NK and CD8+ T cell-Mediated Cytotoxicity of PD-L1-Positive Tumor Cells.","authors":"Mélanie Desbois, Thierry Giffon, Poonam Yakkundi, Carolyn R Denson, Keerthana Sekar, Kevin C Hart, Daniel Santos, Susan E Calhoun, Kathryn Logronio, Sivani Pandey, Dean Ng, Avneesh K Saini, Beatrice T Wang, Bruce A Keyt, Angus M Sinclair, Maya F Kotturi","doi":"10.1158/2326-6066.CIR-24-0937","DOIUrl":"10.1158/2326-6066.CIR-24-0937","url":null,"abstract":"<p><p>IgM antibodies are preformed pentameric or hexameric molecules that can be engineered to generate high-affinity and high-avidity fully human antibody therapeutics. In this study, we report an immunocytokine, IGM-7354, which was designed to bind multiple PD-L1 receptors while trans-presenting a single IL15/IL15Rα complex on the joining chain to IL15Rβγ-expressing cytotoxic NK and CD8+ T cells. We evaluated the pharmacologic and antitumor properties of IGM-7354 in preclinical models. IGM-7354 induced potent proliferation of NK and CD8+ T cells, both in vitro using healthy human peripheral blood mononuclear cells and in vivo in humanized mice, through the IL15/IL15Rα complex. In a mixed-lymphocyte reaction assay with exhausted human T cells, IGM-7354 restored the secretion of IFNγ compared with the IL15/IL15Rα complex or anti-PD-L1 alone, suggesting a rescue of exhausted T cells in vitro. Robust single-agent activity was observed in the humanized PD-L1+ MDA-MB-231 breast cancer mouse model. Antitumor responses were enhanced by adding IGM-7354 to the anti-CD38 daratumumab in RPMI-8226 multiple myeloma or anti-CD19 chimeric antigen receptor T-cell therapies in Raji lymphoma models. Finally, in cynomolgus monkeys, pharmacodynamic activity of increased NK and CD8+ T-cell proliferation was observed in multiple tissue compartments. Taken together, this study demonstrates the feasibility of developing a safe and effective IgM-based immunocytokine for the treatment of cancer, exploiting the multivalency of an IgM antibody to bind PD-L1 with high affinity and avidity and stimulate NK and CD8+ T-cell effectors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1172-1189"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118927","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":"PIKfyve Inhibition Induces Antitumor Immunogenicity by Attenuating STING Trafficking and Lysosomal Degradation.","authors":"Jie He, Rui Huang, Chunyan Zong, Qian Li, Yihao Wang, Guopei Zheng, Yiran Wang, Xiaoyu Yang, Yan Fang, Fengqin Fang, Chunliang Li, Zhe Zhang, Lulu Wang, Lingjie Li, Xiaoliang Jin, Jianfeng Shen","doi":"10.1158/2326-6066.CIR-24-0405","DOIUrl":"10.1158/2326-6066.CIR-24-0405","url":null,"abstract":"<p><p>Significant progress in the application of immune checkpoint blockade for the treatment of multiple types of cancers has been achieved, but its overall response rate and therapeutic efficacy remain unsatisfactory. To address these limitations, the identification of a combinational approach to enhance the therapeutic efficacy of immune checkpoint blockade is needed. The activation of cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) signaling is critical to the induction of antitumor innate immune responses and is a promising target for the development of combinational immunotherapy. In this study, through the Connectivity Map database and a kinase inhibitor library screen using IFN-stimulated genes as a functional readout, we identified PIKfyve as a negative regulator of cGAS-STING signaling. The inhibition of PIKfyve by the kinase inhibitor YM201636 or genetic ablation elicited the expression of IFN-stimulated genes downstream of cGAS-STING and reshaped the antitumor microenvironment by recruiting CD8+ T lymphocytes. In melanoma models, PIKfyve inhibition conferred sensitivity to the combinational therapy of cisplatin and anti-PD-1, which led to a durable treatment response. Depletion of Sting or CD8+ T cells in B16F10 tumors significantly weakened the synergistic effect of PIKfyve inhibition and cisplatin. Mechanistically, PIKfyve interacts with STING to facilitate its trafficking from endosome to lysosome for degradation, thereby suppressing the STING signaling-mediated antitumor activity. These results highlight the importance of maintaining STING signaling as a direction to augment the efficacy of combinational immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1266-1283"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126498","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":"Sustained Macrophage Reprogramming Is Required for CD8+ T cell-Dependent Long-Term Tumor Eradication.","authors":"Carolina Jardim, Marta Bica, Mariana Reis-Sobreiro, Afonso Teixeira da Mota, Raquel Lopes, Miguel Ferreira Pinto, Neuza S Sousa, Sofia Mensurado, Henning Boekhoff, Tommaso Scolaro, Maud Reugebrink, Natacha Goncalves-Sousa, Hiroshi Kubo, Catarina Monteiro Gomes, Catarina Brito, Rafael J Argüello, Elvira P Leites, Vanessa A Morais, Bruno Silva-Santos, Nuno L Barbosa-Morais, Karine Serre","doi":"10.1158/2326-6066.CIR-24-0797","DOIUrl":"10.1158/2326-6066.CIR-24-0797","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAM) exhibit a dual role in tumor progression and antitumor immunity. However, understanding the functional states and molecular mechanisms of antitumor TAMs remains a challenge. Herein, we show that intratumoral administration of a combination of agonists against TLR3 and CD40 [hereafter termed myeloid cell treatment (MCT)] reprogrammed TAMs in situ to adopt a protective antitumor phenotype in an orthotopic mouse breast cancer model, and that this led to tumor regression. Single-cell RNA sequencing of TAMs from different tumor stages and after MCT revealed a transient antitumor TAM phenotype, present at 12 hours after MCT and characterized by markers such as inducible nitric oxide synthase and CD38, which was replaced by TAMs coexpressing tumor-limiting and tumor-promoting features by 72 hours after MCT. Maintenance of antitumor TAMs required repeated MCT administration, and this promoted the activation of CD8+ T cells and long-term tumor eradication. Mechanistically, reactive oxygen species and TNF-α were pivotal in TAM-mediated tumor control. Our findings uncover the vulnerability of transient TAM reprogramming and show that it can be overcome by repeated MCT administrations to sustain efficient antitumor immune responses.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1207-1225"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224379","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":"The Effects of Clinically Relevant Radionuclides on the Activation of an IFN1 Response Correlate with Radionuclide Half-life and Linear Energy Transfer and Influence Radiopharmaceutical Antitumor Efficacy.","authors":"Caroline P Kerr, Julia Sheehan-Klenk, Joseph J Grudzinski, David P Adam, Thanh Phuong T Nguyen, Carolina A Ferreira, Amber M Bates, Won Jong Jin, Ohyun Kwon, Aeli P Olson, Wilson Lin, Meredith Hyun, Justin C Jagodinsky, Maria Powers, Raghava N Sriramaneni, Paul A Clark, Amanda G Shea, Hansel Comas Rojas, Cynthia Choi, Christopher F Massey, Luke M Zangl, Anatoly N Pinchuk, Eduardo Aluicio-Sarduy, KyungMann Kim, Jonathan W Engle, Reinier Hernandez, Bryan P Bednarz, Jamey P Weichert, Zachary S Morris","doi":"10.1158/2326-6066.CIR-24-1191","DOIUrl":"10.1158/2326-6066.CIR-24-1191","url":null,"abstract":"<p><p>Radiopharmaceutical therapies (RPT) activate an IFN1 response in tumor cells. We hypothesized that the timing and amplitude of this response varies by isotope. We compared equal doses delivered by 90Y, 177Lu, and 225Ac in vitro as unbound radionuclides and in vivo when chelated to NM600, a tumor-selective alkylphosphocholine. Response in murine MOC2 head and neck carcinoma and B78 melanoma was evaluated by using qPCR and flow cytometry. Therapeutic response to 225Ac-NM600 + anti-CTLA4 + anti-PD-L1 immune checkpoint inhibition (ICI) was evaluated in wild-type and stimulator of IFN genes (STING) knockout B78. The timing and magnitude of the IFN1 response correlated with radionuclide half-life and linear energy transfer. The ratio of CD8+ T cells to regulatory T cells increased in tumors 7 days after 90Y- and 177Lu-NM600 and on day 21 after 225Ac-NM600. 225Ac-NM600 + ICI improved survival in mice with wild-type but not STING knockout tumors when compared with monotherapies. Thus, we have found that the immunomodulatory effects of RPT vary with radioisotope and promote tumor cell STING-dependent enhanced response to ICIs in murine models. These findings have implications for the optimization of RPT-immunotherapy combinations and could guide the relative timing of therapies, the selection of isotope, and patient selection through tumor biomarkers.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1190-1206"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172951","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":"TCR-Based Therapy Directed against Kallikrein-Related Peptidase 4 Is Safe and Effective against Prostate Cancer.","authors":"Rosa A van Amerongen, Sander Tuit, Dennis F G Remst, Anne K Wouters, Sterre L Siekman, Renate S Hagedoorn, Dirk M van der Steen, Michel G D Kester, Arnoud H de Ru, Geertje van der Horst, Masashi Matsuda, Fumihiko Ishikawa, Peter A van Veelen, J H Frederik Falkenburg, Mirjam H M Heemskerk","doi":"10.1158/2326-6066.CIR-24-0119","DOIUrl":"10.1158/2326-6066.CIR-24-0119","url":null,"abstract":"<p><p>The efficacy of most immunotherapies for prostate cancer is limited by poor tumor immunogenicity as evidenced by minimal T-cell infiltration. Treatment with T cells engineered to express T-cell receptors (TCR) targeting prostate-specific antigens offers a potential solution by bypassing endogenous T-cell repertoire limitations. Through differential gene expression analysis, we have identified kallikrein-related peptidases 2, 3, and 4 (KLK2, KLK3, and KLK4) and homeobox B13 (HOXB13) as strictly prostate lineage-specific genes with high expression in prostate cancer and no expression in healthy tissues of risk. Naturally processed peptides derived from these antigens were identified, enabling T-cell enrichment using peptide-MHC multimers. High-avidity T cells targeting these antigens were isolated from allogeneic HLA-mismatched donors. After screening for on-target tumor specificity and absence of off-target reactivity, TCRs recognizing KLK4 in HLA-A*02:01 and KLK3 in HLA-B*35:01 were sequenced and further tested. TCRs were expressed in T cells through TCR gene transfer and TCRs with best performance were selected. Using combinatorial peptide library scanning, the cross-reactive potential of the KLK4-A2 and KLK3-B35 TCRs was analyzed. The KLK3-B35 TCR exhibited cross-reactivity against two additional peptides derived from LOXHD1 and CDH23, with broad tissue expression, and was therefore excluded. The KLK4-A2 TCR was highly specific for the KLK4 peptide. Further testing confirmed effective cytotoxic killing potential of KLK4-A2 TCR in vitro and in vivo, underscoring its therapeutic potential. These findings highlight the promise of the KLK4-A2 TCR for prostate cancer immunotherapy and demonstrate that prostate-specific antigens can be effectively targeted using TCR gene transfer strategies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1145-1159"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092862","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":"Nanobody-Directed CEA-Targeting CAR T Cells Eliminate Gastrointestinal Cancer Xenografts.","authors":"Zijie Feng, Xuyao Zhang, Zhicheng Peng, Azin Aghamajidi, Yuan Wu, Xianxin Hua","doi":"10.1158/2326-6066.CIR-24-0137","DOIUrl":"10.1158/2326-6066.CIR-24-0137","url":null,"abstract":"<p><p>Gastrointestinal cancers (GIC), including gastric cancers and colorectal cancers, are among the leading causes of cancer-related deaths worldwide. Metastatic gastric cancers and colorectal cancers often develop resistance or fail to respond to current therapies. Adoptive T-cell immunotherapy, especially with T cells expressing chimeric antigen receptors (CAR) targeting CD19, has revolutionized leukemia treatment. However, the development of CAR T-cell therapy for GICs is still in progress. In this study, we used a sequentially tumor-selected antibody and antigen retrieval system to isolate a nanobody that directs CAR T cells to attack gastrointestinal tumor cells in preclinical mouse models. The nanobody VHHB30 specifically binds to the N-terminal (nonglycosylated) domain of carcinoembryonic antigens (CEA). The resulting VHHB30-CAR T cells (CEACAR T cells) exhibited cytotoxicity against both colorectal cancer and gastric cancer cell lines in vitro in a CEA-dependent manner. Moreover, third-generation CEACAR T cells showed enhanced antitumor activity compared with second-generation CEACAR T cells. Furthermore, in vivo studies demonstrated that the CEACAR T cells eradicated various colorectal and gastric tumor xenografts in preclinical mouse models, highlighting a promising approach for CAR T-cell therapy development in GICs through unbiased in vivo selection of potent VHH binders.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1160-1171"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172948","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":"Tumor Cell-Intrinsic Decr2 Regulates Ferroptosis and Immunotherapy Efficacy.","authors":"Shuyin Li, Jason W Shapiro, Hardik Shah, Emily F Higgs, Lishi Xie, Yaopeng Li, Yuanyuan Zha, Jonathan Trujillo, Alexandra Cabanov, Tyler A Jones, Blake Flood, Ken Hatogai, Ruxandra Tonea, Justin Kline, Thomas F Gajewski","doi":"10.1158/2326-6066.CIR-24-0519","DOIUrl":"10.1158/2326-6066.CIR-24-0519","url":null,"abstract":"<p><p>Immune checkpoint blockade therapies have transformed the landscape of cancer care, but durable clinical responses are achieved in only a subset of patients. To identify genes that can contribute to immunotherapy resistance, a genome-wide CRISPR screen was performed. Selection for mutants that are resistant to T cell-mediated killing identified the gene encoding Decr2, a peroxisomal 2,4-dienoyl-CoA reductase. We show that Decr2 in tumor cells participates in CD8+ T cell-mediated tumor cell killing and that Decr2 knockdown reduces the efficacy of anti-PD-L1 therapy in vivo. Knocking down Decr2 expression resulted in diminished ferroptosis that was associated with reduced induction of polyunsaturated ether phospholipids. Analysis of tumor RNA sequencing data from patients with melanoma revealed that upregulation of Decr2 was associated with anti-PD-1 efficacy, and patients with Decr2 gene deletions showed worse clinical outcomes. Our results identify Decr2 as a regulator of immunomediated tumor cell killing, with implications for improving immunotherapy efficacy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1284-1302"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282449","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":"10.1158/2326-6066.CIR-24-0467","url":null,"abstract":"<p><p>Cytotoxic T lymphocytes screen cells for signs of infection and transformation by recognizing peptides displayed on MHC class I molecules. Next to canonical ATG-initiated open reading frames (ORF), noncanonical translation can result in synthesis of nonconventional or \"cryptic\" polypeptides. These can originate from translation initiation at noncanonical 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. In this study, we studied the impact of localization of a CTG-initiated ORF relative to a canonical ATG start codon on 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. The 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 noncanonical start codon-driven cryptic antigen translation and highlights its potential for cancer immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1246-1265"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314520/pdf/","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":"OA","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":"10.1158/2326-6066.CIR-24-0876","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy is an effective treatment strategy for 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, including through direct induction of T cell-effector dysfunction. In this study, 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 nonresponse. To overcome putative VEGF-induced CAR T-cell dysfunction and deliver local VEGF blockade, we generated CAR T cells that secrete a VEGF-targeting single-chain variable fragment to block T-cell and tumor-derived VEGF within the tumor microenvironment. 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 single-chain variable fragment-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":"1132-1144"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","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}

{"title":"A Dendritic Cell-Like Transition of T Cells Is Associated with Spontaneous Remission of Adult T-Cell Leukemia-Lymphoma.","authors":"Miho Watanabe, Jun-Ichirou Yasunaga, Osama Hussein, Azusa Tanaka, Takafumi Shichijo, Mikiko Izaki, Yuki Okamoto, Yoshihiro Komohara, Masao Matsuoka","doi":"10.1158/2326-6066.CIR-24-0306","DOIUrl":"10.1158/2326-6066.CIR-24-0306","url":null,"abstract":"<p><p>Spontaneous remission in patients with various cancers has been reported. Some patients with adult T-cell leukemia-lymphoma (ATL) have experienced spontaneous remission, although the mechanisms for this remain unknown. In this study, we analyzed ATL cells and human T-cell leukemia virus type 1 (HTLV-1)- infected cells using cytometry by time-of-flight mass spectrometry. We observed a small number (less than 5% on average) of ATL cells and HTLV-1-infected cells that expressed CD14 and other dendritic cell (DC)-associated molecules such as CD1c, CD11b, CD11c, and CD141. Single-cell analysis revealed that these T cells expressing DC markers also contained rearranged T-cell receptor genes, indicating that these cells are indeed derived from T cells. In a patient with ATL who entered remission after contracting coronavirus disease 2019, the number of DC-like T cells increased, and an enzyme-linked immunosorbent spot assay detected CTLs against the Tax protein in accordance with a regression of ATL. These findings suggest that DC-like ATL cells acquire antigen-presenting capability and induce spontaneous remission through enhanced immunity to the virus. Specifically, in an ATL cell line, enforced expression of IRF8 and PU.1, in addition to endogenous BATF3 expression, increased CD86 expression and enabled the cells to present Tax peptide antigens to T cells. Collectively, these data indicate that ATL cells acquire antigen-presenting activity when IRF8, PU.1, and BATF3 are expressed, suggesting that the transition of a subset of T cells to DC-like T cells can induce immune responses to viral antigens, resulting in spontaneous remission. Thus, the transition of T cells to DC-like T cells is a unique mechanism for spontaneous remission in ATL.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1098-1110"},"PeriodicalIF":8.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977747","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}