Jonas Lehmann, Martin Thelen, Christoph Kreer, Simon Schran, Maria A Garcia-Marquez, Igor Cisic, Klara Siepmann, Elena M Hagen, Hans Nikolaus Caspar Eckel, Philipp Lohneis, Stephan Kruger, Stefan Boeck, Steffen Ormanns, Martina Rudelius, Jens Werner, Felix Popp, Florian Klein, Michael S von Bergwelt-Baildon, Christiane J Bruns, Alexander Quaas, Kerstin Wennhold, Hans A Schlößer
{"title":"Tertiary Lymphoid Structures in Pancreatic Cancer are Structurally Homologous, Share Gene Expression Patterns and B-cell Clones with Secondary Lymphoid Organs, but Show Increased T-cell Activation.","authors":"Jonas Lehmann, Martin Thelen, Christoph Kreer, Simon Schran, Maria A Garcia-Marquez, Igor Cisic, Klara Siepmann, Elena M Hagen, Hans Nikolaus Caspar Eckel, Philipp Lohneis, Stephan Kruger, Stefan Boeck, Steffen Ormanns, Martina Rudelius, Jens Werner, Felix Popp, Florian Klein, Michael S von Bergwelt-Baildon, Christiane J Bruns, Alexander Quaas, Kerstin Wennhold, Hans A Schlößer","doi":"10.1158/2326-6066.CIR-24-0299","DOIUrl":"10.1158/2326-6066.CIR-24-0299","url":null,"abstract":"<p><p>Tertiary lymphoid structures (TLS) in cancer are considered ectopic hotspots for immune activation that are similar to lymphoid follicles in secondary lymphoid organs (SLO). This study elucidates shared and TLS/SLO-specific features in pancreatic ductal adenocarcinoma (PDAC). TLS abundance was related to superior survival and T-cell abundance in 110 treatment-naïve PDAC samples, underlining their clinical relevance. Immunofluorescence microscopy identified structural homologies between TLSs and SLOs. In RNA expression analyses of laser-microdissected TLSs and paired SLOs, we observed largely overlapping expression patterns of immune-related gene clusters but distinct expression patterns of T-cell and complement-associated genes. Immune cells in TLS expressed essential markers of germinal center formation. Increased activation of tumor-draining lymph nodes in patients with high numbers of TLSs highlights the relevance of these tumor-related structures to systemic immune response. In line with this, we identified an overlap of expanded B-cell receptor clonotypes in TLSs and SLOs, which suggests a vivid cross-talk between the two compartments. We conclude that combined therapeutic approaches exploiting TLS-mediated antitumor immune responses may improve susceptibility of PDAC to immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"323-336"},"PeriodicalIF":8.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805902","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}
Michelle C Buri, Mohamed R Shoeb, Aleksandr Bykov, Peter Repiscak, Hayeon Baik, Alma Dupanovic, Faith O David, Boris Kovacic, Faith Hall-Glenn, Sara Dopa, Jos Urbanus, Lisa Sippl, Susanne Stofner, Dominik Emminger, Jason Cosgrove, Dagmar Schinnerl, Anna R Poetsch, Manfred Lehner, Xaver Koenig, Leïla Perié, Ton N Schumacher, Dagmar Gotthardt, Florian Halbritter, Eva M Putz
{"title":"Natural Killer Cell-Mediated Cytotoxicity Shapes the Clonal Evolution of B-cell Leukemia.","authors":"Michelle C Buri, Mohamed R Shoeb, Aleksandr Bykov, Peter Repiscak, Hayeon Baik, Alma Dupanovic, Faith O David, Boris Kovacic, Faith Hall-Glenn, Sara Dopa, Jos Urbanus, Lisa Sippl, Susanne Stofner, Dominik Emminger, Jason Cosgrove, Dagmar Schinnerl, Anna R Poetsch, Manfred Lehner, Xaver Koenig, Leïla Perié, Ton N Schumacher, Dagmar Gotthardt, Florian Halbritter, Eva M Putz","doi":"10.1158/2326-6066.CIR-24-0189","DOIUrl":"10.1158/2326-6066.CIR-24-0189","url":null,"abstract":"<p><p>The term cancer immunoediting describes the dual role by which the immune system can suppress and promote tumor growth and is divided into three phases: elimination, equilibrium, and escape. The role of NK cells has mainly been attributed to the elimination phase. Here, we show that NK cells play a role in all three phases of cancer immunoediting. Extended co-culturing of DNA-barcoded mouse BCR/ABLp185+ B-cell acute lymphoblastic leukemia (B-ALL) cells with NK cells allowed for a quantitative measure of NK cell-mediated immunoediting. Although most tumor cell clones were efficiently eliminated by NK cells, a certain fraction of tumor cells harbored an intrinsic primary resistance. Furthermore, DNA barcoding revealed tumor cell clones with secondary resistance, which stochastically acquired resistance to NK cells. NK cell-mediated cytotoxicity put a selective pressure on B-ALL cells, which led to an outgrowth of primary and secondary resistant tumor cell clones, which were characterized by an IFNγ signature. Besides well-known regulators of immune evasion, our analysis of NK cell-resistant tumor cells revealed the upregulation of genes, including lymphocyte antigen 6 complex, locus A (Ly6a), which we found to promote leukemic cell resistance to NK cells. Translation of our findings to the human system showed that high expression of LY6E on tumor cells impaired their physical interaction with NK cells and led to worse prognosis in patients with leukemia. Our results demonstrate that tumor cells are actively edited by NK cells during the equilibrium phase and use different avenues to escape NK cell-mediated eradication.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"430-446"},"PeriodicalIF":8.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789615","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":"Spatial Organization of Macrophages in CTL-Rich Hepatocellular Carcinoma Influences CTL Antitumor Activity.","authors":"Yulan Weng, Lu Wang, Yuting Wang, Junyu Xu, Xiaoli Fan, Shufeng Luo, Qiaomin Hua, Jing Xu, Gaoteng Liu, Kai-Bo Zhao, Chang-An Zhao, Dong-Ming Kuang, Chong Wu, Limin Zheng","doi":"10.1158/2326-6066.CIR-24-0589","DOIUrl":"10.1158/2326-6066.CIR-24-0589","url":null,"abstract":"<p><p>Despite the pivotal role of CTLs in antitumor immunity, a substantial proportion of CTL-rich patients with hepatocellular carcinoma (HCC) experience early relapse or immunotherapy resistance. However, spatial immune variations impacting the heterogeneous clinical outcomes of CTL-rich HCCs remain poorly understood. In this study, we compared the single-cell and spatial landscapes of 20 CTL-rich HCCs with distinct prognoses using multiplexed in situ staining and validated the prognostic value of myeloid spatial patterns in a cohort of 386 patients. Random forest and Cox regression models identified macrophage aggregation as a distinctive spatial pattern characterizing a subset of CTL-rich HCCs with an immunosuppressive microenvironment and poor prognosis. Integrated analysis of single-cell and spatial transcriptomics, combined with in situ staining validation, revealed that spatial aggregation enhanced protumoral macrophage reprogramming in HCCs, marked by lipid metabolism orientation, M2-like polarization, and increased adjacent CTL exhaustion. This spatial effect on macrophage reprogramming was replicated in HCC-conditioned human macrophage cultures, which showed an enhanced capability to suppress CTLs. Notably, increased macrophage aggregation was associated with higher response rates to anti-PD-1 immunotherapy. These findings suggest that the spatial distribution of macrophages is a biomarker of their functional diversities and microenvironment status, which holds prognostic and therapeutic implications.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"310-322"},"PeriodicalIF":8.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913843","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}
Nicholas A Maskalenko, Sam Zahroun, Oxana Tsygankova, Nadia Anikeeva, Yuri Sykulev, Kerry S Campbell
{"title":"The FcγRIIIA (CD16) L48-H/R Polymorphism Enhances NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity by Promoting Serial Killing.","authors":"Nicholas A Maskalenko, Sam Zahroun, Oxana Tsygankova, Nadia Anikeeva, Yuri Sykulev, Kerry S Campbell","doi":"10.1158/2326-6066.CIR-24-0384","DOIUrl":"10.1158/2326-6066.CIR-24-0384","url":null,"abstract":"<p><p>Many tumor-specific monoclonal antibody therapies stimulate antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells through FcγRIIIa (CD16). The efficacy of these ADCC-based immunotherapies is potentiated in patients with the common CD16 polymorphic variant F158-V that increases the binding affinity between the receptor and the IgG Fc domain. However, other CD16 variants are less well characterized. Here, we report that CD16 L48-H and L48-R variants both significantly enhance in vitro ADCC responses in primary NK cells and NK-92 cells. During ADCC responses, NK cells expressing CD16 48-H killed and disengaged from target cells faster than those expressing CD16 48-L, resulting in improved serial killing of tumor cells. We found that CD16 48-H also formed an immunologic synapse with a more compact interface, as well as more robust intracellular calcium signaling and quicker polarization of cytolytic vesicles. The ADCC response observed occurs due to increased cytolytic signaling and target cell disengagement, which drives NK cell-mediated serial killing of tumor cells. The L48-H/R polymorphism has potential to benefit patient responses to cancer antibody therapies and may also potentiate antitumor ADCC responses if incorporated into adoptive NK cell therapeutic platforms.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"417-429"},"PeriodicalIF":8.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811753","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}
Zezhuo Su, Maximus Chun Fai Yeung, Shan Han, Raymond Ching Hing Yau, Ying Lee Lam, Kenneth Wai Yip Ho, Tony Wai Shek, Feng Shi, Shuang Feng, Hongtai Chen, Joshua Wing Kei Ho, ZhiYuan Xu, Jason Pui Yin Cheung, Kelvin Sin Chi Cheung
{"title":"Denosumab Enhances antitumour Immunity by Suppressing SPP1 and Boosting Cytotoxic T Cells.","authors":"Zezhuo Su, Maximus Chun Fai Yeung, Shan Han, Raymond Ching Hing Yau, Ying Lee Lam, Kenneth Wai Yip Ho, Tony Wai Shek, Feng Shi, Shuang Feng, Hongtai Chen, Joshua Wing Kei Ho, ZhiYuan Xu, Jason Pui Yin Cheung, Kelvin Sin Chi Cheung","doi":"10.1158/2326-6066.CIR-24-1094","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1094","url":null,"abstract":"<p><p>Denosumab, a RANKL inhibitor, is primarily used to prevent osteoclastogenesis in the treatment of conditions such as osteoporosis, bone metastasis, and giant cell tumour of bone (GCTB). RANKL also plays an important role in immunity by activating NF-κB and its target genes, including the osteopontin-coding gene SPP1 (also known as OPN), which is linked to CXCL9:SPP1 macrophage polarization and prognosis. In this study, we explored an additional role of denosumab in enhancing antitumour immunity in patients. Single-cell RNA sequencing was performed on nine human GCTB samples, including six untreated and three treated only with denosumab, to exclude confounding treatment factors linked with bone metastasis samples. We further analysed paired pre- and post-denosumab treated samples from a cohort of nine GCTB patients and conducted a pan-cancer analysis of 34 distinct types of cancers. Our single-cell analysis of GCTB resulted in a comprehensive cell atlas revealing an antitumour role of denosumab in inhibiting SPP1 expression and augmenting active cytotoxic T cell abundance. Furthermore, we validated this immunomodulatory role of denosumab using the paired GCTB samples. Finally, the pan-cancer analysis supported a negative correlation between SPP1 and CD8A levels, with the CD8A:SPP1 ratio correlating with overall survival in 14 cancer types, which was superior to either CD8A or SPP1 alone. Our research provides clinical evidence that denosumab improves antitumour immunity by decreasing SPP1 expression and enhancing cytotoxic T cell activity, serving as a milestone in the development of innovative use of denosumab and offering potential benefits to patients with elevated levels of SPP1.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514766","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}
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 Wheeler, Anne E Cress, Gregory C Rogers, Justin E Wilson, Alejandro Recio-Boiles, Noel A Warfel
{"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 Wheeler, 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 (ICIs) have changed the treatment paradigm for many cancers but have not shown benefit in prostate cancer (PCa). Chronic inflammation contributes to the immunosuppressive prostate tumor microenvironment (TME) and is associated with poor response to ICIs. The primary source of inflammatory cytokine production is the inflammasome. Here, we identify PIM kinases as regulators of inflammasome activation in tumor-associated macrophages (TAMs). Analysis of clinical data from a cohort of treatment naïve, hormone-responsive PCa patients revealed that tumors from patients with high PIM1/2/3 displayed an immunosuppressive TME 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 PCa. 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 PCa 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 PCa.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nestor Prieto-Dominguez, Paran Goel, Oluwagbemiga A Ojo, Katarina Moretto, Alisha Holtzhausen, Angel Humphryes, Xinyue Zhou, Valeriya Kuznetsova, Francesca Dempsey, Kelly Pittman, Rui Lu, Todd J Green, Lewis Z Shi, Robert S Welner, H Shelton Earp, Eric Ubil
{"title":"PTP inhibition improves the macrophage anti-tumor immune response and the efficacy of chemo- and radiotherapy.","authors":"Nestor Prieto-Dominguez, Paran Goel, Oluwagbemiga A Ojo, Katarina Moretto, Alisha Holtzhausen, Angel Humphryes, Xinyue Zhou, Valeriya Kuznetsova, Francesca Dempsey, Kelly Pittman, Rui Lu, Todd J Green, Lewis Z Shi, Robert S Welner, H Shelton Earp, Eric Ubil","doi":"10.1158/2326-6066.CIR-24-0335","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0335","url":null,"abstract":"<p><p>Traditional anti-cancer therapies induce tumor cell death and subsequent release of Damage Associated Molecular Patterns (DAMPs) that activate the innate inflammatory response. Paradoxically, after treatment, macrophages often adopt a pro-wound healing, rather than pro-inflammatory, phenotype and contribute to cancer progression. We found that in areas proximal to DAMP release, tumor cells upregulate the expression of Pros1. Tumor-secreted Pros1 binds to the macrophage Mer receptor, consequently limiting responsiveness to DAMPs by preventing Toll Like Receptor (TLR) signal transduction. Pharmacological inhibition of PTP1b signaling downstream of Mer rescued the pro-inflammatory response, even in the presence of Pros1. Combining PTP inhibition with traditional therapeutics, like chemo- or radiotherapy, rescued the innate immune response to DAMPs, increased immune infiltration, and resulted in a 40-90% reduction in tumor growth in multiple treatment refractory preclinical models. Our findings suggest using PTP1b inhibitors may be a tumor agnostic means of improving the efficacy of some of the most widely used anti-cancer therapeutic agents.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398063","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}
Mitchell T McGinty, Audrey M Putelo, Sree H Kolli, Tzu-Yu Feng, Madison R Dietl, Cara N Hatzinger, Simona Bajgai, Mika K Poblete, Francesca N Azar, Anwaruddin Mohammad, Pankaj Kumar, Melanie R Rutkowski
{"title":"TLR5 signaling causes dendritic-cell dysfunction and orchestrates failure of immune checkpoint therapy against ovarian cancer.","authors":"Mitchell T McGinty, Audrey M Putelo, Sree H Kolli, Tzu-Yu Feng, Madison R Dietl, Cara N Hatzinger, Simona Bajgai, Mika K Poblete, Francesca N Azar, Anwaruddin Mohammad, Pankaj Kumar, Melanie R Rutkowski","doi":"10.1158/2326-6066.CIR-24-0513","DOIUrl":"10.1158/2326-6066.CIR-24-0513","url":null,"abstract":"<p><p>Ovarian cancer accounts for more deaths than any other cancer of the female reproductive system. Patients who have ovarian tumors infiltrated with high frequencies of T cells are associated with a greater survival probability. However, therapies to revitalize tumor-associated T cells, such as PD-L1/PD-1 or CTLA4 blockade, are ineffective for the treatment of ovarian cancer. In this study, we demonstrate that for ovarian cancer, Toll-Like Receptor 5 (TLR5) signaling, for which the only known ligand is bacterial flagellin, governed failure of PD-L1 and CTLA4 blockade. Mechanistically, chronic TLR5 signaling on CD11c+ cells in vivo and in vitro impaired the differentiation of functional IL-12-producing XCR1+CD103+ conventional type 1 dendritic cells (cDC1), biasing CD11c+ precursor cells toward myeloid subsets expressing high levels of PD-L1. This culminated in impaired activation of CD8+ T cells, reducing CD8+ T-cell function and ability to persist within the ovarian tumor microenvironment. Expansion of cDC1s in situ using FLT3L in combination with PD-L1 blockade achieved significant survival benefit in TLR5 knockout mice bearing ovarian tumors, whereas no benefit was observed in the presence of TLR5 signaling. Thus, we have identified a host-intrinsic mechanism leading to the failure of PD-L1 blockade for ovarian cancer, demonstrating that chronic TLR5 signaling on CD11c+ cells is a barrier limiting the efficacy of checkpoint therapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390163","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}
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
{"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":"https://doi.org/10.1158/2326-6066.CIR-24-0103","url":null,"abstract":"<p><p>The tumor microenvironment (TME) in solid tumors contains myeloid cells that modulate local immune activity. STING signaling activation in these myeloid cells enhances local type I interferon (IFN) production, inducing an innate immune response that mobilizes adaptive immunity and reprograms immunosuppressive myeloid populations to drive antitumor immunity. Here, we generated TAK-500, an immune cell directed antibody drug conjugate (iADC), to deliver a STING agonist to CCR2+ human cells and drive enhanced antitumor activity relative to non-targeted STING agonists. Preclinically, TAK-500 triggered dose-dependent innate immune activation in vitro. In addition, a murine TAK-500 iADC surrogate enhanced innate and adaptive immune responses both in vitro and in murine tumor models. Spatially resolved analysis of CCR2 and immune cell markers in the TME of >1,000 primary human tumors showed 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":""},"PeriodicalIF":8.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment.","authors":"Ayaka Tsuge, Sho Watanabe, Akihito Kawazoe, Yosuke Togashi, Kota Itahashi, Mari Masuda, Atsuo Sai, Shogo Takei, Hiromi Muraoka, Shuichi Ohkubo, Daisuke Sugiyama, Yue Yan, Shota Fukuoka, Toshihiko Doi, Kohei Shitara, Shohei Koyama, Hiroyoshi Nishikawa","doi":"10.1158/2326-6066.CIR-24-0713","DOIUrl":"10.1158/2326-6066.CIR-24-0713","url":null,"abstract":"<p><p>Regulatory T (Treg) cells play key roles in cancer immunity by suppressing a range of antitumor immune responses and contributing to resistance to PD-1 blockade therapy. Given their critical roles in self-tolerance, local control of immunosuppression by Treg cells, such as in the tumor microenvironment, has been intensively studied. Inhibition of HSP90, a chaperone with vital roles in regulating proteostasis in cancer cells, impedes cancer progression by interrupting oncogenic signaling pathways and potentially modulating antitumor immunity, but we have very little mechanistic insight into these immune modulatory effects. In this study, we show that the number of Treg cells is selectively reduced by the HSP90 inhibitor pimitespib in animal models and patients with gastric cancer in a clinical trial (EPOC1704). Pimitespib reduced the highly immunosuppressive human FOXP3high effector Treg cells by inhibiting their proliferation and decreasing their expression of effector molecules, which improved the priming and activation of antigen-specific CD8+ T cells. Mechanistic studies revealed that pimitespib selectively degraded STAT5, a key transducer of the IL2 signaling pathway, which is essential for Treg cell development and maintenance, and consequently compromised FOXP3 expression, leading to selective impairment of immunosuppression in the tumor microenvironment by Treg cells. Thus, pimitespib treatment combined with PD-1 blockade exhibited a far stronger antitumor effect than either treatment alone in animal models. Through these data, we propose that HSP90 inhibition is a promising therapeutic option for Treg cell-targeted cancer immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"273-285"},"PeriodicalIF":8.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738522","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}
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