Cancer immunology research最新文献

{"title":"The effects of clinically relevant radionuclides on the activation of a type I interferon 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":"https://doi.org/10.1158/2326-6066.CIR-24-1191","url":null,"abstract":"<p><p>Radiopharmaceutical therapies (RPT) activate a type I interferon (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 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 interferon genes knockout (STING KO) 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 (Treg) increased in tumors 7 days after 90Y- and 177Lu-NM600 and day 21 after 225Ac-NM600. 225Ac-NM600+ICI improved survival in mice with wild-type but not with STING KO tumors, relative to 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":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1158/2326-6066.CIR-24-0137","url":null,"abstract":"<p><p>Gastrointestinal cancers (GICs), including gastric cancers (GCs) and colorectal cancers (CRCs), are among the leading causes of cancer-related deaths worldwide. Metastatic GCs and CRCs 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. Here, we used a Sequentially Tumor-selected Antibody and Antigen Retrieval (STAR) system to isolate a nanobody that directs CAR T cells to attack GI tumor cells in preclinical mouse models. The nanobody VHHB30 specifically binds to the N-terminal (non-glycosylated) domain of carcinoembryonic antigen (CEA). The resulting VHHB30-CAR T cells (CEACARTs) exhibited cytotoxicity against both CRC and GC cell lines in vitro in a CEA-dependent manner. Moreover, third-generation CEACARTs showed enhanced antitumor activity compared to second-generation CEACARTs. Further, in vivo studies demonstrated that the CEACARTs 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":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-29","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":"IGM-7354, an immunocytokine with IL-15 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":"https://doi.org/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 IL-15/IL-15Rα complex on the joining chain to IL-15Rβγ-expressing cytotoxic natural killer (NK) and CD8+ T-cells. We evaluated the pharmacological and anti-tumor properties of IGM-7354 in preclinical models. IGM-7354 induced potent proliferation of NK and CD8+ T-cells, both in vitro using healthy human PBMCs and in vivo in humanized mice, through the IL-15/IL-15Rα complex. In a mixed-lymphocyte reaction assay with exhausted human T-cells, IGM-7354 restored the secretion of IFNγ compared to the IL-15/IL-15Rα 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. Anti-tumor responses were enhanced by adding IGM-7354 to the anti-CD38 daratumumab in RPMI-8226 multiple myeloma or anti-CD19 CAR 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":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1158/2326-6066.CIR-24-0405","url":null,"abstract":"<p><p>Significant progress in the application of immune checkpoint blockade (ICB) 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 ICB is needed. The activation of cyclic GMP-AMP synthase-stimulator of interferon 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. Here, through the Connectivity Map database and a kinase inhibitor library screen using interferon-stimulated genes (ISGs) 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 ISGs downstream of cGAS-STING and reshapes the antitumor microenvironment by recruiting CD8+ T lymphocytes. In melanoma models, PIKfyve inhibition conferred sensitivity to the combinational therapy of cisplatin and anti-PD1, which lead to a durable treatment response. Depletion of Sting or CD8+ T cells in B16F10 tumor 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 efficacies of combinational immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-22","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":"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":"https://doi.org/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, 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, 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":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-19","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":"Identification of the distinct immune microenvironment features associated with progression following high dose melphalan and autologous stem cell transplant in multiple myeloma.","authors":"Parvathi Sudha, Travis S Johnson, Habib Hamidi, Ke Yang, Enze Liu, Brent Smith, Vivek Chopra, Michael Nixon, Faiza Zafar, Sherif S Farag, Gareth J Morgan, Ola Landgren, Kelvin Lee, Attaya Suvannasankha, Magdalena Czader, Rafat Abonour, Mohammad Abu Zaid, Brian A Walker","doi":"10.1158/2326-6066.CIR-25-0019","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0019","url":null,"abstract":"<p><p>A key treatment for patients with multiple myeloma is high-dose melphalan followed by autologous stem cell transplant (ASCT). It can provide a deep response with long-term remission. However, some patients progress quickly, and it is not clear why that is. Here, we performed single-cell RNA and T-cell receptor (TCR) sequencing of the immune microenvironment of 40 patients before and after ASCT to determine if differences in the immune composition could define those who would progress. Clear differences in cell populations were identified in progressors, including increased T-cell infiltration, decreased TCR diversity, and decreased frequency of monocytes and CD56bright NK cells. We identified cell interactions that predicted progression including increased frequency of CD8+ exhausted T cells and stromal cells and decreased frequency of CD56bright NK cells and plasmacytoid dendritic cells. We propose and validate a model of progression that can also be determined by flow cytometry. Together these data highlight the importance of the immune microenvironment in understanding responses to ASCT.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974034","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":"USP15 Facilitates Colorectal Cancer Immune Evasion through SMYD3/CCL2-Dependent Myeloid-Derived Suppressor Cell Recruitment.","authors":"Shuling Han, Luying Cui, Bojun Wang, Yuli Ruan, Mengde Shi, Chang Hong, Xin Guan, Zhuo Chen, Yingjue Li, Yuanyu Liao, Ming Ma, Xiaolin Lu, Hong Wang, Yanqiao Zhang, Chao Liu","doi":"10.1158/2326-6066.CIR-24-1194","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1194","url":null,"abstract":"<p><p>Colorectal cancer (CRC) creates a suppressive tumor immune microenvironment (TIME) which leads to tumor progression and resistance to immune checkpoint inhibitor (ICI) therapy. Ubiquitin-specific peptidase 15 (USP15) broadly regulates immune responses and immune cell differentiation, but its involvement in shaping the TIME of CRC remains unclear. This study demonstrated that USP15 is over-expressed in CRC and correlated with poor prognosis. Employing colon orthotopic and metastatic tumor models, we performed loss- and gain-of-function assays for USP15, and revealed that over-expression of USP15 promotes tumor progression by increasing the abundance of myeloid-derived suppressor cells (MDSCs) and decreasing the presence of CD8+T cells in the TME. Through in vitro co-culture models and rescue experiments, we observed that tumoral USP15 decreased T cell abundance by promoting MDSC recruitment rather than directly affecting T cells. Mechanistically, we found that USP15 deubiquitinated SMYD3, thereby activating H3K4me3-mediated transcription and release of CCL2, which subsequently recruited MDSCs. Treatment with a USP15 inhibitor improved the efficacy of programmed cell death protein-1 (PD-1) blockade in CRC models. In a cohort of CRC patients undergoing immunotherapy, we observed that those with high USP15 expression had a poor response to anti-PD-1 therapy. In summary, this research explored how USP15 facilitates the recruitment of MDSCs and identified it as a promising target for enhancing immunotherapy in CRC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962080","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":"Somatic mutations in HLA class genes and antigen presenting molecules in malignant glioma.","authors":"Sara C Schulte, Wolfgang Peter, Georg Rosenberger, Moritz Schäfer, Cecile L Maire, Alessandra Rünger, Alice Ryba, Kristoffer Riecken, Krystian D Fita, Jakob Matschke, Nuray Akyüz, Judith Dierlamm, Gunnar W Klau, Franz L Ricklefs, Jens Gempt, Manfred Westphal, Katrin Lamszus, Alexander Dilthey, Malte Mohme","doi":"10.1158/2326-6066.CIR-24-0419","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0419","url":null,"abstract":"<p><p>Immune evasion is a hallmark of gliomas, yet the genetic mechanisms by which tumors escape immune surveillance remain incompletely understood. In this study, we systematically examined the presence of somatic mutations in human leukocyte antigen (HLA) genes and genes encoding proteins involved in antigen-presentation across isocitrate dehydrogenase wild-type (IDHwt) and mutant (IDHmut) gliomas using targeted next-generation sequencing (NGS). To address the challenges associated with detecting somatic mutations in these highly polymorphic and complex regions of the genome, we applied a combination of short-read and long-read sequencing techniques, extended the genetic region of interest (exons and introns), and applied a tailored bioinformatics analysis pipeline, which enabled an accurate evaluation of comprehensive sequencing data. Our analysis identified mutations in HLA class II and non-classical HLA genes as well as genes associated with antigen presentation, such as TAP1/2 and B2M. Three-dimensional modeling of individual mutations simulated the potential impact of somatic mutations in TAP1 and B2M on the encoded protein configuration. The presence of somatic mutations supports the role of antigen-presenting genes in the pathophysiology and potential immune escape of gliomas. Our data demonstrated an increased frequency of such mutations in recurrent glioblastoma (GBM), potentially resulting from a positive selection or mutagenic enrichment of tumor cells during tumor progression. Taken together, this research generates new insights and hypotheses for the functional analysis and optimization of immunotherapy strategies for gliomas, which may guide personalized treatment paradigms.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954635","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":"Selective STING Activation in Intratumoral Myeloid Cells via CCR2-Directed Antibody-Drug Conjugate TAK-500.","authors":"Vicky A Appleman, Atsushi Matsuda, Michelle L Ganno, Dong Mei Zhang, Emily Rosentrater, Angel E Maldonado Lopez, Angelo Porciuncula, Tiquella Hatten, Camilla L Christensen, Samantha A Merrigan, Hong Myung Lee, Min Young Lee, Charlotte I Wang, Linlin Dong, Jian Huang, Natasha Iartchouk, Jianing Wang, He Xu, Tomoki Yoneyama, Konstantin I Piatkov, Satyajeet Haridas, Carole E Harbison, Richard C Gregory, Alexander Parent, Neil Lineberry, Chris Arendt, Kurt A Schalper, Adnan O Abu-Yousif","doi":"10.1158/2326-6066.CIR-24-0103","DOIUrl":"10.1158/2326-6066.CIR-24-0103","url":null,"abstract":"<p><p>The tumor microenvironment in solid tumors contains myeloid cells that modulate local immune activity. Stimulator of IFN gene (STING) signaling activation in these myeloid cells enhances local type-I IFN production, inducing an innate immune response that mobilizes adaptive immunity and reprograms immunosuppressive myeloid populations to drive antitumor immunity. In this study, we generated TAK-500, an immune cell-directed antibody-drug conjugate, to deliver a STING agonist to CCR2+ human cells and drive enhanced antitumor activity relative to nontargeted STING agonists. Preclinically, TAK-500 triggered dose-dependent innate immune activation in vitro. In addition, a murine TAK-500 immune cell-directed antibody-drug conjugate surrogate enhanced innate and adaptive immune responses both in in vitro and murine tumor models. Spatially resolved analysis of CCR2 and immune cell markers in the tumor microenvironment of >1,000 primary human tumors showed that the CCR2 protein was predominantly expressed in intratumoral myeloid cells. Collectively, these data highlight the clinical potential of delivering a STING agonist to CCR2+ cells.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"661-679"},"PeriodicalIF":8.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363743","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":"Inhibition of PIM Kinase in Tumor-Associated Macrophages Suppresses Inflammasome Activation and Sensitizes Prostate Cancer to Immunotherapy.","authors":"Amber N Clements, Andrea L Casillas, Caitlyn E Flores, Hope Liou, Rachel K Toth, Shailender S Chauhan, Kai Sutterby, Sachin Kumar Deshmukh, Sharon Wu, Joanne Xiu, Alex Farrell, Milan Radovich, Chadi Nabhan, Elisabeth I Heath, Rana R McKay, Noor Subah, Sara Centuori, Travis J Weeler, Anne E Cress, Gregory C Rogers, Justin E Wilson, Alejandro Recio-Boiles, Noel A Warfel","doi":"10.1158/2326-6066.CIR-24-0591","DOIUrl":"10.1158/2326-6066.CIR-24-0591","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) have changed the treatment paradigm for many cancers but have not shown benefit in prostate cancer. Chronic inflammation contributes to the immunosuppressive prostate tumor microenvironment and is associated with poor response to ICIs. The primary source of inflammatory cytokine production is the inflammasome. In this study, we identify the proviral integration site for Moloney murine leukemia virus (PIM) kinases as regulators of inflammasome activation in tumor-associated macrophages (TAM). The analysis of clinical data from a cohort of patients with treatment-naïve, hormone-responsive prostate cancer revealed that tumors from patients with high PIM1/2/3 displayed an immunosuppressive tumor microenvironment characterized by high inflammation and a high density of repressive immune cells, most notably TAMs. Macrophage-specific knockout of PIM reduced tumor growth in syngeneic models of prostate cancer. Transcriptional analyses indicated that eliminating PIM from macrophages enhanced the adaptive immune response and increased cytotoxic immune cells. Combined treatment with PIM inhibitors and ICIs synergistically reduced tumor growth. Immune profiling revealed that PIM inhibitors sensitized prostate cancer tumors to ICIs by increasing tumor suppressive TAMs and increasing the activation of cytotoxic T cells. Our data implicate macrophage PIM as a driver of inflammation that limits ICI potency and provide preclinical evidence that PIM inhibitors are an effective strategy to improve the ICI efficacy in prostate cancer.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"633-645"},"PeriodicalIF":8.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467170","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}