Yushen Du, Ramin Salehi-Rad, Tian-Hao Zhang, William P Crosson, Jensen Abascal, Dongdong Chen, Yuan Shi, Hong Jiang, Yen-Wen Tseng, Xi Ma, Mengying Hong, Sihan Wang, Xijuan Wang, Kejun Tang, Shiyao Hu, Yuting Li, Shaokai Ni, Yiqi Cai, Shahed Tappuni, Yong Shen, Bin Liu, Ren Sun
{"title":"Hyper-Interferon Sensitive Influenza Induces Adaptive Immune Responses and Overcomes Resistance to Anti-PD-1 in Murine Non-Small Cell Lung Cancer.","authors":"Yushen Du, Ramin Salehi-Rad, Tian-Hao Zhang, William P Crosson, Jensen Abascal, Dongdong Chen, Yuan Shi, Hong Jiang, Yen-Wen Tseng, Xi Ma, Mengying Hong, Sihan Wang, Xijuan Wang, Kejun Tang, Shiyao Hu, Yuting Li, Shaokai Ni, Yiqi Cai, Shahed Tappuni, Yong Shen, Bin Liu, Ren Sun","doi":"10.1158/2326-6066.CIR-23-1075","DOIUrl":"10.1158/2326-6066.CIR-23-1075","url":null,"abstract":"<p><p>Despite recent advances in immunotherapy with immune checkpoint inhibitors, many patients with non-small cell lung cancer (NSCLC) fail to respond or develop resistance after an initial response. In situ vaccination (ISV) with engineered viruses has emerged as a promising antigen-agnostic strategy that can both condition the tumor microenvironment and augment antitumor T-cell responses to overcome immune resistance. We engineered a live attenuated viral vaccine, hyper-IFN-sensitive (HIS) virus, by conducting a genome-wide functional screening and introducing eight IFN-sensitive mutations in the influenza genome to enhance host IFN response. Compared with wild-type influenza, HIS replication was attenuated in immunocompetent hosts, enhancing its potential as a safe option for cancer therapy. HIS ISV elicited robust yet transient type I IFN responses in murine NSCLCs, leading to an enrichment of polyfunctional effector Th1 CD4+ T cells and cytotoxic CD8+ T cells into the tumor. HIS ISV demonstrated enhanced antitumor efficacy compared with wild-type in multiple syngeneic murine models of NSCLC with distinct driver mutations and varying mutational burden. This efficacy was dependent on host type 1 IFN responses and T lymphocytes. HIS ISV overcame resistance to anti-PD-1 in LKB1-deficient murine NSCLC, resulting in improved overall survival and systemic tumor-specific immunity. These studies provide compelling evidence to support further clinical evaluation of HIS as an \"off-the-shelf\" ISV strategy for patients with NSCLC refractory to immune checkpoint inhibitors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1765-1779"},"PeriodicalIF":8.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342194","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}
Zhen Zhang, Xuan Zhao, Qitai Zhao, Xinfeng Chen, Congcong Li, Yaqing Liu, Chunyi Shen, Lijie Song, Lijun Miao, Fuyou Guo, Xiaoning Mou, Jie Zhao, Weiyue Gu, Yi Zhang
{"title":"Peripheral Blood-Derived PD-1/CD28-CD19 CAR-Modified PD-1+ T-Cell Therapy in Patients with Solid Tumors.","authors":"Zhen Zhang, Xuan Zhao, Qitai Zhao, Xinfeng Chen, Congcong Li, Yaqing Liu, Chunyi Shen, Lijie Song, Lijun Miao, Fuyou Guo, Xiaoning Mou, Jie Zhao, Weiyue Gu, Yi Zhang","doi":"10.1158/2326-6066.CIR-24-0037","DOIUrl":"10.1158/2326-6066.CIR-24-0037","url":null,"abstract":"<p><p>T cells expressing programmed cell death 1 (PD-1) in the peripheral blood (PB) of patients with tumors possess therapeutic potential; however, the immunosuppressive, PD-1-triggered signaling pathway and limited proliferative capacity of PD-1+ T cells present challenges to their therapeutic application. Here, we observed no discernible distinction between PD-1+ and PD-1- T cells in terms of clonal overlap. However, CD8+PD-1+ T cells from PB and tumor tissues exhibited tighter clustering based on clone size. Single-cell RNA sequencing analysis showed that PD-1+ T cells from PB highly expressed cytotoxicity-related genes and were enriched for T-cell activation-related pathways compared with PD-1- T cells from PB or tumor tissues. Consistent with this, PB-derived PD-1+ T cells exhibited strong cytotoxicity toward autologous tumor cells and tumor cell lines. To augment PD-1+ T-cell activity against solid tumors in vivo, we introduced a PD-1/CD28 fusion receptor combined with a CD19 chimeric antigen receptor into PD-1+ T cells, which were then expanded in vitro. The modified PD-1+ T cells exhibited superior proliferation and antitumor abilities in vitro. In addition, four patients with cancer were infused with autologous PD-1/CD28-CD19 chimeric antigen receptor PD-1+ T cells. None of these patients experienced severe side effects, and one patient with melanoma achieved a complete response that was maintained for 6.7 months. The three other patients had stable disease. Collectively, these results suggested that cell therapy with modified PB-derived PD-1+ T cells is both safe and effective, and it may constitute a promising treatment strategy for patients with cancer.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1703-1717"},"PeriodicalIF":8.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280527","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":"Blocking WNT7A Enhances MHC-I Antigen Presentation and Enhances the Effectiveness of Immune Checkpoint Blockade Therapy.","authors":"Jiazheng Sun, Pin Wang, Ziying Yi, Yushen Wu, Yuxian Wei, Huiying Fang, Daqiang Song, Yuru Chen, Huimin Du, Jing Huang, Qin Li, Dejuan Yang, Guosheng Ren, Hongzhong Li","doi":"10.1158/2326-6066.CIR-24-0484","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0484","url":null,"abstract":"<p><p>The limited infiltration of CD8+ T cells in tumors hampers the effectiveness of T cell-based immunotherapy, yet the mechanisms that limit tumor infiltration by CD8+ T cells remain unclear. Through bulk RNA sequencing of human tumors, we identified a strong correlation between WNT7A expression and reduced CD8+ T-cell infiltration. Further investigation demonstrated that inhibiting WNT7A substantially enhanced MHC-I expression on tumor cells. Mechanistically, WNT7A inhibition inactivated Wnt/β-catenin signaling pathway and thus resulted in reduced physical interaction between β-catenin and p65 in the cytoplasm, which increased the nuclear translocation of p65 and activated the NF-κB pathway, ultimately promoting the transcription of genes encoding MHC-I molecules. We found that our lead compound, 1365-0109, disrupted the protein-protein interaction between WNT7A and its receptor FZD5, resulting in the upregulation of MHC-I expression. In murine tumor models, both genetic and pharmaceutical suppression of WNT7A led to increased MHC-I levels on tumor cells, and consequently enhanced the infiltration and functionality of CD8+ T cells, which bolstered antitumor immunity and improved the effectiveness of immune checkpoint blockade therapy. These findings have elucidated the intrinsic mechanisms of WNT7A-induced immune suppression, suggesting that therapeutic interventions targeting WNT7A hold promise for enhancing the efficacy of immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738521","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":"An Engineered Self-biomineralized Oncolytic Adenovirus Induces Effective Antitumor Immunity and Synergizes With Immune Checkpoint Blockade.","authors":"Shibing Wang, Xue Yang, Ying-Yu Ma, Junjie Wu, Ketao Jin, Ruibo Zhao, Hai Zou, Xiaozhou Mou","doi":"10.1158/2326-6066.CIR-23-0957","DOIUrl":"10.1158/2326-6066.CIR-23-0957","url":null,"abstract":"<p><p>Oncolytic adenoviruses (oADV) are promising cancer treatment agents. However, in vivo hepatic sequestration and the host immunologic response against the agents limit the therapeutic potential of oADVs. In this study, we present a combined method with a rational design for improving oADV infection efficiency, immunogenicity, and treatment efficacy by self-biomineralization. We integrated the biomimetic nucleopeptide W6p into the capsid of oADV using reverse genetics, allowing calcium phosphate mineralization to be biologically induced on the surface of oADV under physiologic conditions, resulting in a mineral exterior. This self-biomineralized, modified oADV (oADV-W6-CaP) enhanced infection efficiency and therapeutic efficacy in coxsackievirus and adenovirus receptor (CAR)-negative cancer cells wherein protecting them against neutralization by preexisting neutralizing antibodies. In subcutaneous mouse tumor models, systemic injection of oADV-W6-CaP demonstrated improved antitumor effectiveness, which was associated with increased T-cell infiltration and CD8+ T-cell activation. In addition, the anticancer immune response elicited by oADV-W6-CaP was dependent on CD8+ T cells, which mediated long-term immunologic memory and systemic antitumor immunity against the same tumor. Finally, the addition of PD1 or CD47 inhibition boosted the anticancer effects of oADV-W6-CaP and increased the rate of complete tumor clearance in tumor-bearing animals. The self-biomineralized oADV shifted the suppressive tumor microenvironment from a \"cold\" to \"hot\" state and synergized with immune checkpoint blockade to exert outstanding tumoricidal effects, demonstrating promising potential for cancer immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1640-1654"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878431","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}
Xin Zhang, Limei Guo, Wenyu Tian, Ying Yang, Yue Yin, Yaruo Qiu, Weixuan Wang, Yang Li, Guangze Zhang, Xuyang Zhao, Guangxi Wang, Zhiqiang Lin, Meng Yang, Wei Zhao, Dan Lu
{"title":"CD36+ Proinflammatory Macrophages Interact with ZCCHC12+ Tumor Cells in Papillary Thyroid Cancer Promoting Tumor Progression and Recurrence.","authors":"Xin Zhang, Limei Guo, Wenyu Tian, Ying Yang, Yue Yin, Yaruo Qiu, Weixuan Wang, Yang Li, Guangze Zhang, Xuyang Zhao, Guangxi Wang, Zhiqiang Lin, Meng Yang, Wei Zhao, Dan Lu","doi":"10.1158/2326-6066.CIR-23-1047","DOIUrl":"10.1158/2326-6066.CIR-23-1047","url":null,"abstract":"<p><p>Local recurrence and distal metastasis negatively impact the survival and quality of life in patients with papillary thyroid cancer (PTC). Therefore, identifying potential biomarkers and therapeutic targets for PTC is clinically crucial. In this study, we performed a multiomics analysis that identified a subset of CD36+ proinflammatory macrophages within the tumor microenvironment of PTC. The recruitment of CD36+ macrophages to premalignant regions strongly correlated with unfavorable outcomes in PTC, and the presence of tumor-infiltrating CD36+ macrophages was determined to be a risk factor for recurrence. The CD36+ macrophages exhibited interactions with metabolically active ZCCHC12+ tumor cells. By secreting SPP1, the CD36+ macrophages activated the PI3K-AKT signaling pathway, thereby promoting proliferation of the cancer cells. Dysregulation of iodine metabolism was closely related to the acquisition of the pro-inflammatory phenotype in macrophages. Iodine supplementation inhibited the activation of proinflammatory signaling and impeded the development of CD36+ macrophages by enhancing DUSP2 expression. Overall, our findings shed light on the intricate cross-talk between CD36+ macrophages and ZCCHC12+ tumor cells, providing valuable insights for the treatment and prognosis of PTC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1621-1639"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043866","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 Single-Cell Analysis of the NK-Cell Landscape Reveals That Dietary Restriction Boosts NK-Cell Antitumor Immunity via Eomesodermin.","authors":"Junming He, Donglin Chen, Wei Xiong, Yuande Wang, Shasha Chen, Meixiang Yang, Zhongjun Dong","doi":"10.1158/2326-6066.CIR-23-0944","DOIUrl":"10.1158/2326-6066.CIR-23-0944","url":null,"abstract":"<p><p>Abnormal metabolism in tumor cells represents a potential target for tumor therapy. In this regard, dietary restriction (DR) or its combination with anticancer drugs is of interest as it can impede the growth of tumor cells. In addition to its effects on tumor cells, DR also plays an extrinsic role in restricting tumor growth by regulating immune cells. NK cells are innate immune cells involved in tumor immunosurveillance. However, it remains uncertain whether DR can assist NK cells in controlling tumor growth. In this study, we demonstrate that DR effectively inhibits metastasis of melanoma cells to the lung. Consistent with this, the regression of tumors induced by DR was minimal in mice lacking NK cells. Single-cell RNA sequencing analysis revealed that DR enriched a rejuvenated subset of CD27+CD11b+ NK cells. Mechanistically, DR activated a regulatory network involving the transcription factor Eomesodermin (Eomes), which is essential for NK-cell development. First, DR promoted the expression of Eomes by optimizing mTORC1 signaling. The upregulation of Eomes revived the subset of functional CD27+CD11b+ NK cells by counteracting the expression of T-bet and downstream Zeb2. Moreover, DR enhanced the function and chemotaxis of NK cells by increasing the accessibility of Eomes to chromatin, leading to elevated expression of adhesion molecules and chemokines. Consequently, we conclude that DR therapy enhances tumor immunity through nontumor autonomous mechanisms, including promoting NK-cell tumor immunosurveillance and activation.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1508-1524"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987431","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":"Engineered CAR-NK Cells with Tolerance to H2O2 and Hypoxia Can Suppress Postoperative Relapse of Triple-Negative Breast Cancers.","authors":"Yan Liu, Jiahui Chen, Jia Tian, Yu Hao, Xinxing Ma, Yehui Zhou, Liangzhu Feng","doi":"10.1158/2326-6066.CIR-23-1017","DOIUrl":"10.1158/2326-6066.CIR-23-1017","url":null,"abstract":"<p><p>Surgical resection is a primary treatment option for patients with triple-negative breast cancer (TNBC), but it is associated with a high rate of postoperative local and metastatic relapse. Although chimeric antigen receptor-engineered NK (CAR-NK) cell therapy can specifically recognize and eradicate tumor cells, its therapeutic potency toward TNBCs is markedly suppressed by the hostile tumor microenvironment, which restricts the infiltration, survival, and effector functions of CAR-NK cells inside tumor masses. In this study, HER1-overexpressing TNBC-targeted CAR-NK (HER1-CAR-NK) cells were genetically engineered with catalase to endow them with tolerance toward the high levels of oxidative stress and hypoxia inside TNBC tumors through the catalytic decomposition of hydrogen peroxide, which is a principle reactive oxygen species inside tumors, into O2. We refer to these cells as HER1-CAR-CAT-NK cells. Upon intratumoral fixation with an injectable alginate hydrogel, HER1-CAR-CAT-NK cells enabled sustained tumor hypoxia attenuation and exhibited markedly enhanced persistence and effector functions inside TNBC tumors. As a result, locoregional HER1-CAR-CAT-NK cell therapy not only inhibited the growth of local primary residual tumors but also elicited systemic antitumor activity to suppress the growth of distant tumors. This study highlights that genetic engineering of HER1-CAR-NK cells with catalase is a promising strategy to suppress the postoperative local and distant relapse of TNBC tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1574-1588"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632721","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}
Ayush Pant, Aanchal Jain, Yiyun Chen, Kisha Patel, Laura Saleh, Stephany Tzeng, Ryan T Nitta, Liang Zhao, Caren Yu-Ju Wu, Maria Bederson, William Lee Wang, Brandon Hwa-Lin Bergsneider, John Choi, Ravi Medikonda, Rohit Verma, Kwang Bog Cho, Lily H Kim, Jennifer E Kim, Eli Yazigi, Si Yeon Lee, Sakthi Rajendran, Prajwal Rajappa, Crystal L Mackall, Gordon Li, Betty Tyler, Henry Brem, Drew M Pardoll, Michael Lim, Christopher M Jackson
{"title":"The CCR6-CCL20 Axis Promotes Regulatory T-cell Glycolysis and Immunosuppression in Tumors.","authors":"Ayush Pant, Aanchal Jain, Yiyun Chen, Kisha Patel, Laura Saleh, Stephany Tzeng, Ryan T Nitta, Liang Zhao, Caren Yu-Ju Wu, Maria Bederson, William Lee Wang, Brandon Hwa-Lin Bergsneider, John Choi, Ravi Medikonda, Rohit Verma, Kwang Bog Cho, Lily H Kim, Jennifer E Kim, Eli Yazigi, Si Yeon Lee, Sakthi Rajendran, Prajwal Rajappa, Crystal L Mackall, Gordon Li, Betty Tyler, Henry Brem, Drew M Pardoll, Michael Lim, Christopher M Jackson","doi":"10.1158/2326-6066.CIR-24-0230","DOIUrl":"10.1158/2326-6066.CIR-24-0230","url":null,"abstract":"<p><p>Regulatory T cells (Treg) are important players in the tumor microenvironment. However, the mechanisms behind their immunosuppressive effects are poorly understood. We found that CCR6-CCL20 activity in tumor-infiltrating Tregs is associated with greater glycolytic activity and ablation of Ccr6 reduced glycolysis and lactic acid production while increasing compensatory glutamine metabolism. Immunosuppressive activity toward CD8+ T cells was abrogated in Ccr6-/- Tregs due to reduction in activation-induced glycolysis. Furthermore, Ccr6-/- mice exhibited improved survival across multiple tumor models compared to wild-type mice and Treg and CD8+ T-cell depletion abrogated the improvement. In addition, Ccr6 ablation further promoted the efficacy of anti-PD-1 therapy in a preclinical glioma model. Follow-up knockdown of Ccl20 with siRNA also demonstrated improvement in antitumor efficacy. Our results unveil CCR6 as a marker and regulator of Treg-induced immunosuppression and identify approaches to target the metabolic determinants of Treg immunosuppressive activity.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1542-1558"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916166","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}
Peter Georgiev, SeongJun Han, Amy Y Huang, Thao H Nguyen, Jefte M Drijvers, Hannah Creasey, Joseph A Pereira, Cong-Hui Yao, Joon Seok Park, Thomas S Conway, Megan E Fung, Dan Liang, Michael Peluso, Shakchhi Joshi, Jared H Rowe, Brian C Miller, Gordon J Freeman, Arlene H Sharpe, Marcia C Haigis, Alison E Ringel
{"title":"Age-Associated Contraction of Tumor-Specific T Cells Impairs Antitumor Immunity.","authors":"Peter Georgiev, SeongJun Han, Amy Y Huang, Thao H Nguyen, Jefte M Drijvers, Hannah Creasey, Joseph A Pereira, Cong-Hui Yao, Joon Seok Park, Thomas S Conway, Megan E Fung, Dan Liang, Michael Peluso, Shakchhi Joshi, Jared H Rowe, Brian C Miller, Gordon J Freeman, Arlene H Sharpe, Marcia C Haigis, Alison E Ringel","doi":"10.1158/2326-6066.CIR-24-0463","DOIUrl":"10.1158/2326-6066.CIR-24-0463","url":null,"abstract":"<p><p>Progressive decline of the adaptive immune system with increasing age coincides with a sharp increase in cancer incidence. In this study, we set out to understand whether deficits in antitumor immunity with advanced age promote tumor progression and/or drive resistance to immunotherapy. We found that multiple syngeneic cancers grew more rapidly in aged versus young adult mice, driven by dysfunctional CD8+ T-cell responses. By systematically mapping immune cell profiles within tumors, we identified loss of tumor antigen-specific CD8+ T cells as a primary feature accelerating the growth of tumors in aged mice and driving resistance to immunotherapy. When antigen-specific T cells from young adult mice were administered to aged mice, tumor outgrowth was delayed and the aged animals became sensitive to PD-1 blockade. These studies reveal how age-associated CD8+ T-cell dysfunction may license tumorigenesis in elderly patients and have important implications for the use of aged mice as preclinical models of aging and cancer.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1525-1541"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072106","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":"Blocking CX3CR1+ Tumor-Associated Macrophages Enhances the Efficacy of Anti-PD1 Therapy in Hepatocellular Carcinoma.","authors":"Xiaonan Xiang, Kai Wang, Hui Zhang, Haibo Mou, Zhixiong Shi, Yaoye Tao, Hongliang Song, Zhengxing Lian, Shuai Wang, Di Lu, Xuyong Wei, Haiyang Xie, Shusen Zheng, Jianguo Wang, Xiao Xu","doi":"10.1158/2326-6066.CIR-23-0627","DOIUrl":"10.1158/2326-6066.CIR-23-0627","url":null,"abstract":"<p><p>The efficacy of immune checkpoint inhibitors in the treatment of hepatocellular carcinoma (HCC) remains limited, highlighting the need for further investigation into the mechanisms underlying treatment resistance. Accumulating evidence indicates that tumor-associated macrophages (TAM) within the tumor microenvironment demonstrate a key role in immune evasion and treatment resistance. This study explored the role of TAMs in the HCC tumor microenvironment. Our findings reveal that TAMs expressing CX3C motif chemokine receptor 1 (CX3CR1) induced T-cell exhaustion through IL27 secretion in orthotopic models of HCC following treatment with anti-PD1. Moreover, we identified prostaglandin E2 (PGE2), released by immune-attacked tumor cells, as a key regulator of TAM transition to a CX3CR1+ phenotype. To augment the therapeutic response to anti-PD1 therapy, we propose targeting CX3CR1+ TAMs in addition to anti-PD1 therapy. Our study contributes to the understanding of the role of TAMs in cancer immunotherapy and highlights potential clinical implications for HCC treatment. The combination of targeting CX3CR1+ TAMs with anti-PD1 therapy holds promise for enhancing the efficacy of immunotherapeutic interventions in patients with HCC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1603-1620"},"PeriodicalIF":8.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901041","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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