Dohyun Park, Inae Park, Bohwa Han, Yujin Baek, Dowon Moon, Noo Li Jeon, Junsang Doh
{"title":"Cytotoxic Chemotherapy in a 3D Microfluidic Device Induces Dendritic Cell Recruitment and Trogocytosis of Cancer Cells.","authors":"Dohyun Park, Inae Park, Bohwa Han, Yujin Baek, Dowon Moon, Noo Li Jeon, Junsang Doh","doi":"10.1158/2326-6066.CIR-24-0263","DOIUrl":"10.1158/2326-6066.CIR-24-0263","url":null,"abstract":"<p><p>Cytotoxic chemotherapy that kills cancer cells can also elicit antitumor immune responses. Therefore, understanding the immunogenic context of cytotoxic chemotherapy can improve combination immunotherapies. In this study, we sought to improve our understanding of dendritic cell (DC) dynamics in cytotoxic chemotherapy-treated tumor tissues by developing three-dimensional (3D) microfluidic devices that enable high-resolution visualization of cellular dynamics. Specifically, microfluidic chips mimicking 3D tumor tissues were fabricated and used. Collagen gel blocks encapsulating cancer cells in microfluidics were treated with various concentrations of oxaliplatin (OXP; 0-40 μg/mL). Then, DCs were attached on the side of the collagen gel blocks, and migration of DCs within the 3D gels was quantitatively analyzed. Interactions between OXP-treated cancer cells and DCs were observed by high-resolution time-lapse imaging. Active infiltration of DCs was predominantly observed when OXP was administrated, indicating OXP-treated cancer cells release factors promoting DC motility. The highest frequency of DC recruitment was detected at a moderate OXP concentration, suggesting that optimizing the dosage of cytotoxic chemotherapy is crucial in order to improve immunogenic cell death. High-resolution video microscopy revealed that DCs employ trogocytosis to disassemble dying/dead cancer cells and acquire antigens, as opposed to phagocytosing the entire cancer cells. Microfluidic chip-based observations may provide new insights for the design of new therapeutic strategies to combine chemotherapy and immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"931-938"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors.","authors":"","doi":"10.1158/2326-6066.CIR-13-6-WWR","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-13-6-WWR","url":null,"abstract":"","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":"13 6","pages":"791"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Eph Receptors Activate Myeloid Checkpoint Receptor LILRB5 to Support Tumor Development.","authors":"Yubo He, Chengcheng Zhang, Lingxiao Tan, Mi Deng, Xiaoye Liu, Ryan Huang, Xing Yang, Jingjing Xie, Qi Lou, Meng Fang, Caroline Smith, Samuel John, Wei Xiong, Xin Li, Cheryl Lewis, Jade Homsi, Ankit Gupta, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang","doi":"10.1158/2326-6066.CIR-24-0737","DOIUrl":"10.1158/2326-6066.CIR-24-0737","url":null,"abstract":"<p><p>Immunosuppressive myeloid cells are critical obstacles to T cell-centered immune checkpoint blockade therapies, which have been successful in treating a fraction of patients with cancer. How tumor cells interact with myeloid cells to regulate immune responses and tumor development is unclear. In this study, we report that certain membrane tyrosine kinase Eph receptors, including EphA7 and EphB1, specifically bind the immune inhibitory receptors leukocyte Ig-like receptor family B 5 (LILRB5) and LILRB2. These Eph receptors induce LILRB5-mediated signaling activation, and LILRB5 also activates Eph receptor signaling. Activation of LILRB5 promoted immunosuppressive marker expression and inhibited activating marker expression on myeloid cells from patients with cancer in vitro. Upon myeloid cell-specific expression of LILRB5 in transgenic mice, the interaction between the Eph receptor on tumor cells and LILRB5 on myeloid cells led to increased tumor growth, increased immunosuppressive myeloid cells, and decreased frequencies of functional T cells compared with control mice. Eph-induced LILRB5 signaling and functions were reversed by LILRB5 blockade. In sum, certain Eph receptors functionally interact with the myeloid checkpoint receptor LILRB5 resulting in bidirectional signaling, and LILRB5 plays an important role in supporting immunosuppressive myeloid cells and sustaining tumor development.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"821-835"},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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}
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}
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":8.2,"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}
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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
