Cancer Immunology, Immunotherapy最新文献

{"title":"Neutrophil-induced pyroptosis promotes survival in patients with hepatoblastoma.","authors":"Tingyi Fu, Jiquan Zhou, Liyuan Yang, Jing Wang, Hui Li, Yuhua Shan, Hongxiang Gao, Chenjie Xie, Dapeng Jiang, Lei Zhang, Ji Ma, Qiuhui Pan, Min Xu, Min Zhang, Song Gu","doi":"10.1007/s00262-024-03922-z","DOIUrl":"10.1007/s00262-024-03922-z","url":null,"abstract":"<p><strong>Background: </strong>Hepatoblastoma (HB) is the predominant hepatic malignancy among children. Despite therapeutic options for HB were gradually refined in recent years, patients with metastasis suffer from an unsatisfactory prognosis. Pyroptosis is a type of programmed and inflammatory necrosis. Neutrophils are crucial in innate immunity, which were shown to be associated with tumor progression. Our study strived to unravel the relationship between neutrophil-induced pyroptosis (NIP) and HB.</p><p><strong>Methods: </strong>The clinical and bulk RNA sequencing data of 38 patients with HB were obtained from Shanghai Children's Medical Center. We established NIP score based on the LASSO regression. The single-cell RNA sequencing data (GSE186975) were used for for key genes identification, cellular communication, and differentiation trajectories of neutrophils. KEGG, GO, GSVA, and ssGSEA enrichment were used to analyze biological functions, including neutrophil extracellular traps (NETs), NOD-like receptors pathway, neutrophil activation, neutrophil-mediated cytotoxicity, and others.</p><p><strong>Results: </strong>We constructed a NIP score based on the expression of three genes related to neutrophil and pyroptosis, namely ELANE, CASP1, and NOD2, which was positively correlated with a favorable prognosis of HB. Moreover, we clarified the function of ELANE in HB microenvironmwnt. Immunohistochemistry and transcriptome analysis unraveled a significant correlation between NETs and pyroptosis in HB, suggesting the key role of NETs-related neutrophils in inducing pyroptosis and prolonging survival. We also found upregulated tumor-promoting and immunosuppression-related pathways in the HB microenvironment. In addition, we clarified the growth trajectories and phenotypic changes of neutrophils in the immune microenvironment of HB, which can serve as potential targets for immunotherapy.</p><p><strong>Conclusions: </strong>The novel NIP score for patients with HB shows high predictive value for survival. Moreover, we identified biological function, cellular communication, and growth trajectories of neutrophils in HB. Our findings broaden insights into the treatment of HB.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 3","pages":"106"},"PeriodicalIF":4.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11813845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and efficacy of neoadjuvant therapy with tislelizumab plus chemotherapy for locally advanced head and neck squamous cell carcinoma: a single-arm, retrospective study.","authors":"Haifeng Liang, Wenting Liang, Jiawang Tian, Shibei Zheng, Yangzhou Su, Piao Huang, Renhui Chen, Zhong Guan, Qian Cai","doi":"10.1007/s00262-025-03953-0","DOIUrl":"10.1007/s00262-025-03953-0","url":null,"abstract":"<p><strong>Background: </strong>Head and neck squamous cell carcinoma (HNSCC) is a very common type of head and neck cancer, and the 5-year overall survival (OS) rate is only 50%. Inhibitors targeting the programmed death 1 (PD-1) pathway have gained widespread clinical adoption. However, the relationship between the infiltration characteristics of immune cells in the tumor immune microenvironment (TIME) and the effect of immunotherapy on HNSCC remains to be explored.</p><p><strong>Methods: </strong>Patients diagnosed with HNSCC who received Tislelizumab combined with chemotherapy were reviewed between February 2021 and March 30, 2024, in our single center. The laryngoscopy, magnetic resonance imaging (MRI), and pathologic response were evaluated to the efficacy of neoadjuvant therapy with Tislelizumab plus chemotherapy treatment. Treatment-related adverse events (TRAEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0.</p><p><strong>Result: </strong>Our analysis involved 42 patients who received Tislelizumab combined with chemotherapy. A total of 18 patients underwent surgical treatment following the completion of immunotherapy combined with chemotherapy. Among them, 6 patients achieved pCR (33%). The 1-year OS rate of the 42 patients enrolled in the study was 95.05%, and the 1-year PFS rate was 89.86%. There was a significant positive correlation between the lymphocyte density in HNSCC prior to the administration of neoadjuvant PD-1 inhibitor therapy combined with chemotherapy and the immunotherapy efficacy. Compared with pretreatment, the neutrophil-to-lymphocyte ratio (NLR) was significantly decreased, and the lymphocyte density was significantly increased in HNSCC patients after immunotherapy.</p><p><strong>Conclusions: </strong>The integration of neoadjuvant PD-1 inhibitor therapy with chemotherapy has been demonstrated to be a safe and effective strategy, can improve the tumor response rate and survival rate, and is a valuable treatment for patients with HNSCC. Furthermore, the study suggests that an elevated NLR within the HNSCC tumor microenvironment could potentially serve as a biomarker indicative of diminished immunotherapy efficacy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 3","pages":"108"},"PeriodicalIF":4.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11813832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chidamide functions as a VISTA/PSGL-1 blocker for cancer immunotherapy.","authors":"Xiaoshuang Niu, Wenshan Zhao, Xiuman Zhou, Feiyu Luo, Youmei Xiao, Tao Luo, Xinghua Sui, Wanqiong Li, Qingyu Dong, Xin Yang, Zhuoying He, Wenzhi Shang, Yixuan Sun, Yanfeng Gao","doi":"10.1007/s00262-025-03955-y","DOIUrl":"10.1007/s00262-025-03955-y","url":null,"abstract":"<p><p>The response rates of PD-1/PD-L1 blockade in cancer immunotherapy are relatively low, necessitating the development of novel immune checkpoint inhibitors. Compared with other immune checkpoints, VISTA interacts with its ligand PSGL-1 only under acidic conditions in the tumor microenvironment to suppress the function of CD8⁺ T cells. On the other hand, drug repurposing offers advantages such as time efficiency and high safety. However, the development of VISTA/PSGL-1 inhibitor based on drug repurposing is still infancy. Here, by screening a library of marketed drugs, we identified Chidamide had a strong binding affinity toward VISTA (K_D = 5 nM) and blocked VISTA/PSGL-1 under acidic conditions, thereby significantly enhancing the function of CD8⁺ T cells and inhibiting the tumor growth in immunocompetent murine CT26 tumor model. This study represents the first discovery of Chidamide as VISTA/PSGL-1 blocker for cancer immunotherapy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 3","pages":"104"},"PeriodicalIF":4.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11813839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early detection of myocarditis caused by immune checkpoint inhibitor therapy with nivolumab and ipilimumab for advanced recurrent renal cell carcinoma.","authors":"Maki Todo, Yodo Gatate, Shintaro Nakano, Go Kaneko, Masayuki Hagiwara, Takayuki Takahashi, Yuta Umezawa, Genji Ueda, Shiho Ishikawa, Yoshinori Makino, Masafumi Oyama, Suguru Shirotake","doi":"10.1007/s00262-025-03945-0","DOIUrl":"10.1007/s00262-025-03945-0","url":null,"abstract":"<p><p>Combination therapy with nivolumab and ipilimumab for advanced renal cell carcinoma (RCC) may cause immune-related myocarditis; however, its incidence in this cancer type and regimen remains unknown. At our institution, we measure biomarkers, such as high-sensitivity Troponin (hsTn), and perform electrocardiograms (ECGs) and echocardiography before and every month after the initiation of this therapy, and the findings obtained and patients' symptoms are continuously monitored by physicians and pharmacists. A retrospective survey was conducted on physiological and biochemical test findings and immune-related adverse events in patients with advanced RCC who received combination therapy with nivolumab and ipilimumab between October 1, 2018 and December 31, 2023. Patients suspected of having myocarditis consulted with cardiologists. Myocarditis due to this therapy was detected in 5 of the 86 patients (5.8%) assessed using the European Society of Cardiology 2022 guidelines. There were no fatal symptoms or death due to myocarditis. The median time to the onset of myocarditis was 25 days (21-86 days). The early detection of myocarditis caused by this therapy requires the monitoring of changes by periodically measuring hsTn and other cardiac markers and performing ECGs and echocardiography from the early stages of administration through to the end of treatment. In addition to checking symptoms, if these abnormalities are detected and myocarditis is suspected, prompt collaboration with cardiologists is recommended. Our management strategy of care by a onco-cardiology team may contribute to the early diagnosis and treatment of myocarditis.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 3","pages":"97"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-injection of exosomes can significantly suppress ovarian cancer growth by activating the immune system in mice.","authors":"Yuanyuan Wang, Changyi Zhang, Huimin Zeng, Liangliang Wang, Zanhong Wang, Zhiqiang Han","doi":"10.1007/s00262-025-03951-2","DOIUrl":"10.1007/s00262-025-03951-2","url":null,"abstract":"<p><p>As a type of \"cold tumor\" with limited immune cell infiltration, ovarian cancer has historically shown limited efficacy in immunotherapy. In this study, we report that exosomes from ovarian cancer can specifically target omentum which is the predilection site for ovarian cancer to metastasize and combat subsequently implanted tumor. Furthermore, we found a substantial increase in the proportion of CD3 + T cells, particularly CD8 + T cells, within the omental tissue where exosomes homed. This increase was accompanied by a significant enhancement in granzyme B levels within CD8 + T cells. Additionally, there was a notable elevation in the concentration of interferon-gamma (IFN-γ) in peripheral blood. In vitro results indicated that exosomes could be internalized by dendritic cells (DCs), promote DC differentiation, and subsequently induce the production of granzyme B and IFN-γ in T cells. Surprisingly, we also observed high expression of programmed death ligand 1 (PD-L1) in the omentum. Therefore, we discovered whether combining PD-L1 blockade led to further tumor regression. However, although the combination group showed complete tumor regression, this difference did not reach statistical significance. But in general, we emphasize that in the case of pre-injection, exosomes have great potential to combat the famous \"cold tumor\", ovarian cancer, via targeting omentum and activating anti-tumor immunity, offering a novel avenue for overcoming ovarian cancer.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 3","pages":"103"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting HVEM-GPT2 axis: a novel approach to T cell activation and metabolic reprogramming in non-small cell lung cancer therapy.","authors":"Yuanshan Yao, Chunji Chen, Bin Li, Wen Gao","doi":"10.1007/s00262-025-03949-w","DOIUrl":"10.1007/s00262-025-03949-w","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The modulation of tumor microenvironments through immune checkpoint pathways is pivotal for the development of effective cancer immunotherapies. This study aims to explore the role of HVEM in non-small cell lung cancer (NSCLC) microenvironment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The lung cancer datasets for this study were directly downloaded from The Cancer Genome Atlas (TCGA). Single-cell data were sourced from the Tumor Immune Single-cell Hub (TISCH). Multiplex immunohistochemistry (mIHC) was used to explore the cellular composition and spatial distribution of HVEM in lung cancer immune microenvironment. The immune microenvironment of HVEM KO mice bearing mouse lung cancer cell was also evaluated. Co-cultured system and phenotype assays facilitated the examination of Jurkat T cells' effect on A549 and H1299 lung cancer cells. Quantitative PCR and Western blotting determined gene and protein expression, respectively, cellular respiration was measured through oxygen consumption rate (OCR) assays. Lung cancer cells co-cultured with Jurkat T cells were xenografted into nude mice to evaluate tumor growth and metastatic potential. Next, RNA-seq, COIP, Dual-luciferase reporter experiment, and CHIP-seq were used to explore the potential underlying mechanism.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In our study, we investigated the role of HVEM in the microenvironment of NSCLC and its implications in immunotherapy. Crucially, HVEM, part of the tumor necrosis factor receptor superfamily, influences T cell activation, potentially impacting immunotherapeutic outcomes. Using the TIDE algorithm, our results showcased a link between HVEM levels and immune dysfunction in NSCLC patients. Delving deeper into the NSCLC microenvironment, we found HVEM predominantly expressed in T cell subpopulations. CD8 + HVEM + and CD4 + HVEM + indicated better prognosis in lung adenocarcinoma tissue microarray using multiplex immunohistochemistry. Activated T cells, particularly from the Jurkat cell line, significantly inhibited NSCLC progression, reducing both proliferation and invasion capabilities of A549 and H1299 lung cancer cell lines. In vivo models reinforced these observations. Manipulating HVEM expression revealed its essential role in T cell survival and activation. In addition, animal experiments revealed the importance of HVEM in maintaining activated peripheral immunity and inflamed local tumor microenvironment. Furthermore, our data suggest that HVEM is pivotal in T cell metabolic reprogramming, transitioning from oxidative phosphorylation to aerobic glycolysis. RNA sequencing illuminated a potential relationship between HVEM and GPT2, an enzyme tied to amino acid metabolism and cellular energetics. Subsequent experiments confirmed that HVEM's influence on T cell activation and metabolism is potentially mediated through its regulation of GPT2. In addition, GATA1 was validated to regulate HVEM expression in activated Jurkat T cells.&lt;/p&gt;&lt;p&gt;&lt;st","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 3","pages":"101"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: potential suppression by pirfenidone.","authors":"Tomohiko Yagi, Shunsuke Kagawa, Shohei Nogi, Atsuki Taniguchi, Masashi Yoshimoto, Kanto Suemori, Yasuo Nagai, Shuto Fujita, Shinji Kuroda, Satoru Kikuchi, Yoshihiko Kakiuchi, Fuminori Teraishi, Kosei Takagi, Toshiaki Ohara, Hiroshi Tazawa, Toshiyoshi Fujiwara","doi":"10.1007/s00262-025-03946-z","DOIUrl":"10.1007/s00262-025-03946-z","url":null,"abstract":"<p><strong>Background: </strong>The mechanisms by which neutrophils acquire pro-tumor properties remain poorly understood. In pancreatic cancer, cancer-associated fibroblasts (CAFs) may interact with neutrophils, directing them to promote tumor progression.</p><p><strong>Methods: </strong>To validate the association between CAFs and neutrophils, the localization of neutrophils was examined in clinically resected pancreatic cancer specimens. CAFs were produced by culturing in cancer-conditioned media, and the effects of these CAFs on neutrophils were examined. In vitro migration and invasion assays assess the effect of CAF-activated neutrophils on cancer cells. The factors secreted by the activated neutrophils were also explored. Finally, pirfenidone (PFD) was tested to determine whether it could suppress the pro-tumor functions of activated neutrophils.</p><p><strong>Results: </strong>In pancreatic cancer specimens, neutrophils tended to co-localize with IL-6-positive CAFs. Neutrophils co-cultured with CAFs increased migratory capacity and prolonged life span. CAF-affected neutrophils enhance the migratory and invasive activities of pancreatic cancer cells. IL-8 is the most upregulated cytokine secreted by the neutrophils. PFD suppresses IL-8 secretion from CAF-stimulated neutrophils and mitigates the malignant traits of pancreatic cancer cells.</p><p><strong>Conclusion: </strong>CAFs activate neutrophils and enhance the malignant phenotype of pancreatic cancer. The interactions between cancer cells, CAFs, and neutrophils can be disrupted by PFD, highlighting a potential therapeutic approach.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 3","pages":"96"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antitumor effects of natural killer cells derived from gene-engineered human-induced pluripotent stem cells on hepatocellular carcinoma.","authors":"Mayuna Nakamura, Yuka Tanaka, Keishi Hakoda, Masahiro Ohira, Tsuyoshi Kobayashi, Kenji Kurachi, Kouichi Tamura, Hideki Ohdan","doi":"10.1007/s00262-025-03940-5","DOIUrl":"10.1007/s00262-025-03940-5","url":null,"abstract":"<p><p>Mortality and recurrence rates of hepatocellular carcinoma (HCC) remain high despite the use of various treatment methods. Recently, cell-based immunotherapy using natural killer (NK) cells has attracted considerable attention in cancer immunotherapy. NK cells generated from induced pluripotent stem cells (iPSCs) are a new option for use as an NK cell resource. The eNK cells (HLCN061, developed by HEALIOS K.K.) are human iPSC-derived NK cells differentiated from clinical-grade iPSCs in which IL-15, CCR2B, CCL19, CD16a, and NKG2D have been introduced. In this study, we aimed to evaluate the potential of eNK cell therapy for HCC treatment. The analysis of eNK cells for cell surface and intracellular molecules revealed that antitumor-related surface molecules (TRAIL, CD226, and CD16) and intracellular cytotoxic factors (perforin, granzyme B, TNFα, and IFNγ) were highly expressed. In addition, eNK cells exhibited high cytotoxicity against HCC cell lines (HepG2, HuH7, and SNU-423), which are sensitive to NKG2D, TRAIL, and CD226. The TRAIL and perforin/granzyme B pathways are largely involved in this cytotoxic mechanism, as indicated by the reduction in cytotoxicity induced by TRAIL inhibitory antibodies and concanamycin A, which inhibits perforin/granzyme B-mediated cytotoxicity. Our data suggest that eNK cells, whose functions have been enhanced by genetic engineering, have the potential to improve HCC treatment.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 3","pages":"99"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PSMA antibody, humanized PSMA.CAR10.3, or Cetuximab increases prostate cancer localization of NF-κB p50-deficient immature myeloid cells (p50-IMC) and phagocytosis by their macrophage progeny.","authors":"Mohammad A Alzubi, Theresa Barberi, Alan D Friedman","doi":"10.1007/s00262-024-03939-4","DOIUrl":"10.1007/s00262-024-03939-4","url":null,"abstract":"<p><p>Adoptive transfer of immature myeloid cells lacking the repressive NF-κB p50 subunit (p50-IMC) slows the growth of syngeneic murine prostate cancer and other tumors. Directing p50-IMC to tumors using Fc receptor-bound antibodies (Abs) or surface chimeric antigen receptors (CARs) may increase tumor localization and subsequent phagocytosis of cancer cells by their mature myeloid progeny, potentiating anti-tumor T cell activation. PSMA and EGFR are found on aggressive human prostate cancers, and p50-IMC express receptors that bind the antibody Fc domain. p50-IMC combined with PSMA Ab, EGFR Ab (Cetuximab), or fully humanized PSMA.CAR10.3 manifest increased localization to Myc-CaP murine prostate cancer tumors expressing PSMA or EGFR. Tumor localization is further increased when myelo-depleting 5-fluorouracil precedes p50-IMC administration. Additionally, we find that PSMA Ab, EGFR Ab, or PSMA.CAR10.3 increase in vitro phagocytosis of Myc-CaP cells expressing PSMA or EGFR by p50-IMC-derived macrophages, including in M2-promoting IL-4, which is a component of the immune-suppressive tumor microenvironment. Lack of tolerance of human PSMA or EGFR by immune-competent mice and lack of expression of human PSMA protein in the prostate of AR₂-Probasin-hPSMA transgenic mice precluded our ability to determine whether human-specific PSMA or EGFR antibody or PSMA.CAR10.3 increases anti-tumor efficacy of murine p50-IMC. Nevertheless, this study indicates the potential clinical utility of adding a tumor-directing antibody or CAR, including the novel, fully humanized PSMA.CAR10.3, to proinflammatory p50-IMC to optimize the activation of anti-tumor immunity in prostate cancer and other malignancies, and understanding PSMA toxicity in normal but not malignant prostate epithelium may reveal a novel therapeutic opportunity.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 3","pages":"95"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive analysis of molecular characteristics of hot and cold tumor of gastric cancer.","authors":"Chenxi Lv, Tianwei Chen, Jiangtao Li, Yuqiang Shan, Hong Zhou","doi":"10.1007/s00262-025-03954-z","DOIUrl":"10.1007/s00262-025-03954-z","url":null,"abstract":"<p><strong>Background: </strong>The advent of immunotherapy has revolutionized the treatment paradigm for gastric cancer (GC), offering unprecedented clinical benefits. However, a detailed molecular characterization of the tumor immune microenvironment in GC is essential to further optimize these therapies and enhance their efficacy.</p><p><strong>Methods: </strong>Consensus clustering was utilized to classify GC patients into distinct immune states, followed by an in-depth analysis of differences in mutation profiles, copy number variations, and DNA methylation patterns. Weighted gene co-expression network analysis (WGCNA) and correlation analysis were applied to identify gene modules underlying the classification of immune \"hot\" and \"cold\" tumors. Subsequently, 101 machine learning algorithm combinations were employed to construct a prognostic model based on the identified gene modules. Single-cell analysis was conducted to investigate cellular interactions associated with the immune-determinant gene module. Finally, immunofluorescence staining for CD8, CD45, and CXCR4 was performed on human GC tissue samples.</p><p><strong>Results: </strong>A total of 1,298 GC patients were included in this comprehensive analysis. For the first time, we identified and characterized immune \"hot\" and \"cold\" tumors in GC patients, revealing distinct molecular features associated with these tumor types. Immune \"hot\" tumor-related genes were identified, and their functional roles were validated through biological behavior analysis. A prognostic signature, termed the hot tumor top regulators (HTTR), was developed using 101 machine learning algorithm combinations. The HTTR signature emerged as an independent prognostic factor, effectively stratifying patients into low- and high-risk groups with significant differences in overall survival. High-risk groups demonstrated strong associations with immune checkpoint regulation, antigen presentation, and inhibitory pathways. Notably, single-cell analysis revealed that HTTR genes were highly active in CD8 + T cells, with the CXCL12-CXCR4 axis playing a critical role in mediating interactions between CD8 + T cells and endothelial cells.</p><p><strong>Conclusion: </strong>In conclusion, the HTTR signature served as a robust prognostic biomarker for GC patients and effectively identified those with immune \"hot\" tumors. This finding provided valuable insights into the molecular mechanisms of tumor immunity in GC, offering potential avenues for targeted therapeutic interventions.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 3","pages":"102"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}