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
{"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}
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
{"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}
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
{"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}
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":"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}
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
{"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}
{"title":"cGAS mRNA-Based Immune Agonist Promotes Vaccine Responses and Antitumor Immunity.","authors":"Yali Qu, Zhibin Li, Jiahao Yin, He Huang, Jialu Ma, Zhelin Jiang, Qian Zhou, Ying Tang, Yuting Li, Minpeng Huang, Zhutian Zeng, Ao Guo, Fang Fang, Yanqiong Shen, Ruibo Zhao, Yucai Wang, Daxing Gao","doi":"10.1158/2326-6066.CIR-24-0804","DOIUrl":"10.1158/2326-6066.CIR-24-0804","url":null,"abstract":"<p><p>mRNA vaccines are a potent tool for immunization against viral diseases and cancer. However, the lack of a vaccine adjuvant limits the efficacy of these treatments. In this study, we used cGAS mRNA, which encodes the DNA innate immune sensor, complexed with lipid nanoparticles (LNP), to boost the immune response. By introducing specific mutations in human cGAS mRNA (hcGASK187N/L195R), we significantly enhanced cGAS activity, resulting in a more potent and sustained stimulator of interferon gene (STING)-mediated IFN response. cGAS mRNA-LNPs exhibited stimulatory effects on maturation, antigen engulfment, and antigen presentation by antigen-presenting cells, both in vitro and in vivo. Moreover, the hcGASK187N/L195R mRNA-LNP combination demonstrated a robust adjuvant effect and amplified the potency of mRNA and protein vaccines, which was a result of strong humoral and cell-mediated responses. Remarkably, the hcGASK187N/L195R mRNA-LNP complex, either alone or in combination with antigens, demonstrated exceptional efficacy in eliciting antitumor immunity. In addition to its immune-boosting properties, hcGASK187N/L195R mRNA-LNP exerted antitumor effects with IFNγ directly on tumor cells, further promoting tumor restriction. In conclusion, we developed a cGAS mRNA-based immunostimulatory adjuvant compatible with various vaccine forms to boost the adaptive immune response and cancer immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"680-695"},"PeriodicalIF":8.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603937","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 Antitumor 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":"10.1158/2326-6066.CIR-24-0335","url":null,"abstract":"<p><p>Traditional anticancer 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 proinflammatory, 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 signal transduction. Pharmacological inhibition of PTP1b signaling downstream of Mer rescued the proinflammatory response, even in the presence of Pros1. Combining protein tyrosine phosphatase (PTP) inhibition with traditional therapeutics, such as chemo- or radiotherapy, rescued the innate immune response to DAMPs, increased immune infiltration, and resulted in a 40% to 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 anticancer therapeutic agents.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"749-766"},"PeriodicalIF":8.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048275/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Laurent Gorvel, Marylou Panouillot, Marie-Sarah Rouvière, Emilien Billon, Stéphane Fattori, Jumaporn Sonongbua, Nicolas Boucherit, Amira Ben Amara, Olivia Quilichini, Samuel Granjeaud, Clara Degos, Jacques A Nunès, Xavier Carcopino, Eric Lambaudie, Anne-Sophie Chrétien, Renaud Sabatier, Marie-Caroline Dieu-Nosjean, Daniel Olive
{"title":"Tertiary Lymphoid Structures Are Associated with Enhanced Macrophage Activation and Immune Checkpoint Expression and Predict Outcome in Cervical Cancer.","authors":"Laurent Gorvel, Marylou Panouillot, Marie-Sarah Rouvière, Emilien Billon, Stéphane Fattori, Jumaporn Sonongbua, Nicolas Boucherit, Amira Ben Amara, Olivia Quilichini, Samuel Granjeaud, Clara Degos, Jacques A Nunès, Xavier Carcopino, Eric Lambaudie, Anne-Sophie Chrétien, Renaud Sabatier, Marie-Caroline Dieu-Nosjean, Daniel Olive","doi":"10.1158/2326-6066.CIR-24-0979","DOIUrl":"10.1158/2326-6066.CIR-24-0979","url":null,"abstract":"<p><p>Cervical tumors are usually treated using surgery, chemotherapy, and radiotherapy and would benefit from immunotherapies. However, the immune microenvironment in cervical cancer remains poorly described. Tertiary lymphoid structures (TLS) were recently described as markers for better immunotherapy response and overall better prognosis in patients with cancer. We evaluated the cervical tumor immune microenvironment, specifically focusing on TLS, using combined high-throughput phenotyping, soluble factor concentration dosage in the tumor microenvironment, and spatial interaction analyses. We found that TLS presence was associated with a more inflammatory soluble microenvironment, with the presence of B cells as well as more activated macrophages and dendritic cells (DC). Furthermore, this myeloid cell activation was associated with the expression of immune checkpoints, such as PD-L1 and CD40, and the proximity of activated conventional type 2 DCs to CD8+ T cells, indicating better immune interactions and tumor control. Finally, we associated TLS presence, greater B-cell density, and activated DC density with improved progression-free survival, substantiating TLS presence as a potential prognostic marker. Our results provide evidence that TLS presence denotes cell activation and immunotherapy target expression.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"712-728"},"PeriodicalIF":8.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070739","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}
Ganesan Ramamoorthi, Marie Catherine Lee, Carly M Farrell, Colin Snyder, Saurabh K Garg, Amy L Aldrich, Vincent Lok, William Dominguez-Viqueira, Sy K Olson-Mcpeek, Marilin Rosa, Namrata Gautam, Shari Pilon-Thomas, Ling Cen, Krithika N Kodumudi, Doris Wiener, Thordur Oskarsson, Ana P Gomes, Robert A Gatenby, Brian J Czerniecki
{"title":"Antitumor CD4+ T Helper 1 Cells Target and Control the Outgrowth of Disseminated Cancer Cells.","authors":"Ganesan Ramamoorthi, Marie Catherine Lee, Carly M Farrell, Colin Snyder, Saurabh K Garg, Amy L Aldrich, Vincent Lok, William Dominguez-Viqueira, Sy K Olson-Mcpeek, Marilin Rosa, Namrata Gautam, Shari Pilon-Thomas, Ling Cen, Krithika N Kodumudi, Doris Wiener, Thordur Oskarsson, Ana P Gomes, Robert A Gatenby, Brian J Czerniecki","doi":"10.1158/2326-6066.CIR-24-0630","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0630","url":null,"abstract":"<p><p>Detection of disseminated cancer cells (DCC) in the bone marrow (BM) of patients with breast cancer is a critical predictor of late recurrence and distant metastasis. Conventional therapies often fail to completely eradicate DCCs in patients. In this study, we demonstrate that intratumoral priming of antitumor CD4+ T helper 1 (Th1) cells was able to eliminate the DCC burden in distant organs and prevent overt metastasis, independent of CD8+ T cells. Intratumoral priming of tumor antigen-specific CD4+ Th1 cells enhanced their migration to the BM and distant metastatic site to selectively target DCC burden. The majority of these intratumorally activated CD4+ T cells were CD4+PD1- T cells, supporting their nonexhaustion stage. Phenotypic characterization revealed enhanced infiltration of memory CD4+ T cells and effector CD4+ T cells in the primary tumor, tumor-draining lymph node, and DCC-driven metastasis site. A robust migration of CD4+CCR7+CXCR3+ Th1 cells and CD4+CCR7-CXCR3+ Th1 cells into distant organs further revealed their potential role in eradicating DCC-driven metastasis. The intratumoral priming of antitumor CD4+ Th1 cells failed to eradicate DCC-driven metastasis in CD4- or IFN-γ knockout mice. Moreover, antitumor CD4+ Th1 cells, by increasing IFN-γ production, inhibited various molecular aspects and increased classical and nonclassical MHC molecule expression in DCCs. This reduced stemness and self-renewal while increasing immune recognition in DCCs of patients with breast cancer. These results unveil an immune basis for antitumor CD4+ Th1 cells that modulate DCC tumorigenesis to prevent recurrence and metastasis in patients.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":"13 5","pages":"729-748"},"PeriodicalIF":8.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984231","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 Antitumor 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":"10.1158/2326-6066.CIR-24-1094","url":null,"abstract":"<p><p>Denosumab, a RANK ligand inhibitor, is primarily used to prevent osteoclastogenesis in the treatment of conditions such as osteoporosis, bone metastasis, and giant cell tumor of bone (GCTB). RANK ligand 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 antitumor 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 analyzed paired samples collected before and after denosumab treatment from a cohort of nine patients with GCTB 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 antitumor 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 antitumor 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":"646-660"},"PeriodicalIF":8.1,"publicationDate":"2025-05-02","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}
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