{"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}
Sheng Wang, Duo Xu, Yuan Wang, Yuehua Zhou, Lingyan Xiao, Fang Li, Jingyao Tu, Wan Qin, Sidan Tian, Bolong Zheng, Yihua Wang, Xiang-Lin Yuan, Yuanhui Liu, Bo Liu
{"title":"A Bifunctional Antibody Targeting PD-1 and TGF-β Signaling Has Antitumor Activity in Combination with Radiotherapy and Attenuates Radiation-Induced Lung Injury.","authors":"Sheng Wang, Duo Xu, Yuan Wang, Yuehua Zhou, Lingyan Xiao, Fang Li, Jingyao Tu, Wan Qin, Sidan Tian, Bolong Zheng, Yihua Wang, Xiang-Lin Yuan, Yuanhui Liu, Bo Liu","doi":"10.1158/2326-6066.CIR-23-0903","DOIUrl":"10.1158/2326-6066.CIR-23-0903","url":null,"abstract":"<p><p>Radio-immunotherapy has antitumor activity but also causes toxicity, which limits its clinical application. JS-201 is a dual antibody targeting PD-1 and TGF-β signaling. We investigated the antitumor effect of JS-201 combined with radiotherapy (RT) and the effect on radiation-induced lung injury (RILI). Different tumor models were established to detect the antitumor effects of the combination of JS-201 and RT, and RILI models were established to observe the effects of JS-201. Transcriptome sequencing showed that JS-201 optimized the tumor microenvironment by inhibiting extracellular matrix formation and angiogenesis. Combining JS-201 with RT further increased the inflammatory response and immune infiltration and showed great abscopal effects in Lewis lung cancer luciferase-positive models. Single-cell sequencing demonstrated that JS-201 reduced fibroblast proliferation by inhibiting the TGF-β/Smad pathway and the release of neutrophil extracellular traps mediated by ROS, thereby relieving radiation-induced pulmonary fibrosis. In conclusion, the JS-201 and RT combination enhances antitumor effects while mitigating acute and chronic RILI, and it may have potential for translational investigation as a cancer treatment strategy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"767-784"},"PeriodicalIF":8.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058266","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}
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, 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 XCR1+CD103+ conventional type 1 dendritic cells in situ using Flt3L-Ig 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":"696-711"},"PeriodicalIF":8.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048257/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lihaoyun Huang, Cangang Zhang, Aimin Jiang, Anqi Lin, Lingxuan Zhu, Weiming Mou, Dongqiang Zeng, Zaoqu Liu, Bufu Tang, Jian Zhang, Quan Cheng, Kai Miao, Ting Wei, Peng Luo
{"title":"T-cell Senescence in the Tumor Microenvironment.","authors":"Lihaoyun Huang, Cangang Zhang, Aimin Jiang, Anqi Lin, Lingxuan Zhu, Weiming Mou, Dongqiang Zeng, Zaoqu Liu, Bufu Tang, Jian Zhang, Quan Cheng, Kai Miao, Ting Wei, Peng Luo","doi":"10.1158/2326-6066.CIR-24-0894","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0894","url":null,"abstract":"<p><p>T-cell senescence occurs in the tumor microenvironment (TME) and influences cancer outcomes as well as the effectiveness of immunotherapies. The TME triggers this T-cell senescence via multiple pathways, including persistent stimulation with tumor-associated antigens, altered metabolic pathways, and activation of chronic inflammatory responses. Senescent T cells exhibit characteristics such as genomic instability, loss of protein homeostasis, metabolic dysregulation, and epigenetic alterations. Direct cross-talk between senescent T cells and other immune cells further exacerbates the immunosuppressive TME. This immune-tumor cell interaction within the TME contributes to impaired tumor antigen recognition and surveillance by T cells. The presence of senescent T cells is often associated with poor prognosis and reduced efficacy of immunotherapies; thus, targeting the tumor-promoting mechanisms of T-cell senescence may provide novel insights into improving tumor immunotherapy and patient outcomes. This review explores the contributors to tumor-derived T-cell senescence, the link between T-cell senescence and tumor prognosis, and the potential for targeting T-cell senescence to enhance tumor immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":"13 5","pages":"618-632"},"PeriodicalIF":8.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962084","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}
Ming Fang, Yaling Li, Peng Wang, Yanan Wang, Xiaoqian Wang, Xiaoxia Wa, Yu Zhang, Zhenyu He, Jiawei Li, Ling Li, Yun Su, Huinian Zhou, Jianzheng He, Yongqi Liu
{"title":"METTL3 inhibition restores PD-L1 expression and CD8+ T-cell cytotoxic function in immunotherapy treated gastric cancer.","authors":"Ming Fang, Yaling Li, Peng Wang, Yanan Wang, Xiaoqian Wang, Xiaoxia Wa, Yu Zhang, Zhenyu He, Jiawei Li, Ling Li, Yun Su, Huinian Zhou, Jianzheng He, Yongqi Liu","doi":"10.1158/2326-6066.CIR-24-1179","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1179","url":null,"abstract":"<p><p>The efficacy of immunotherapy targeting PD-1/PD-L1 in gastric cancer (GC) depends on PD-L1 expression level and infiltration of immune cells within the tumor microenvironment (TME). While methyltransferase-like 3 (METTL3) plays a role in the development and progression of GC, its mechanism of regulating the TME in GC remains unclear. In this study, we demonstrated that expression of PD-L1 is regulated by METTL3. We found that METTL3 mediated m6A modification of PDL1 mRNA in the 3'-untranslated region (UTR) and induced mRNA degradation through an m6A/YTHDF2-dependent pathway in human GC cells. METTL3-knockdown or inhibition in GC cells significantly enhanced Jurkat cell migration and cytotoxic activity. In clinical GC tissue, a negative correlation was observed between the expression levels of PD-L1 and those of METTL3 or YTHDF2. In vivo, combination treatment with the METTL3 inhibitor STM2457 and PD-1 monoclonal antibody (mAb) resulted in a significant reduction in tumor growth, enhanced PD-L1 expression, and increased the infiltration of CD8+ T cells. Finally, lower METTL3 expression in tumors correlated with improved sensitivity to anti-PD-1 immunotherapy in patients. Our findings revealed that METTL3-mediated m6A modification of PDL1 mRNA levels represents an epigenetic mechanism regulating anti-tumor immunity in GC, and inhibiting METTL3 during PD-1 mAb treatment reshaped the TME, thereby establishing a promising treatment approach for enhancing immunotherapy efficacy in GC patients.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972842","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}
Yizhe Sun, Andrea Rodgers Furones, Okan Gultekin, Shruti Khare, Shi Yong Neo, Wenyang Shi, Lidia Moyano-Galceran, Kong-Peng Lam, Ramanuj Dasgupta, Jonas Fuxe, Sahar Salehi, Kaisa Lehti, Dhifaf Sarhan
{"title":"Adaptive NK Cells Exhibit Tumor-Specific Immune Memory and Cytotoxicity in Ovarian Cancer.","authors":"Yizhe Sun, Andrea Rodgers Furones, Okan Gultekin, Shruti Khare, Shi Yong Neo, Wenyang Shi, Lidia Moyano-Galceran, Kong-Peng Lam, Ramanuj Dasgupta, Jonas Fuxe, Sahar Salehi, Kaisa Lehti, Dhifaf Sarhan","doi":"10.1158/2326-6066.CIR-24-0852","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0852","url":null,"abstract":"<p><p>Adaptive Natural Killer (aNK) cells have emerged as a subset of NK cells with memory-like properties and specific cytotoxicity, offering promising therapeutic potential in cancer immunotherapy. In this study, we explored the role of aNK cells in high-grade serous ovarian cancer (HGSOC), focusing on their ability to establish tumor-specific immune memory and effectively target autologous tumors. Through a combination of in silico, in vitro, and ex vivo approaches, we demonstrated that aNK cells, in contrast to conventional NK (cNK) cells, exhibit recall responses, specific cytotoxicity, and preferential infiltration into the tumor microenvironment (TME). Our data revealed that aNK cells interact with dendritic cells (DCs) within the TME via the HLA-E/NKG2C axis and CXCR2 signaling, contributing to their memory formation and tumor-targeting capabilities. These findings suggest that aNK cells could serve as potent agents in NK cell-based immunotherapies, particularly in solid tumors like HGSOC, where they resist immunosuppressive signals and maintain robust anti-tumor activity. This study provides new insights into the adaptive-like properties of aNK cells, underscoring their potential for advancing cancer immunotherapy strategies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978841","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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