Journal for Immunotherapy of Cancer最新文献

{"title":"Antibodies against the multifaceted cathepsin D protein open new avenues for TNBC immunotherapy.","authors":"Pénélope Desroys du Roure, Timothée David, Aude Mallavialle, Valérie Laurent-Matha, Pascal Roger, Séverine Guiu, Thierry Chardès, Emmanuelle Liaudet-Coopman","doi":"10.1136/jitc-2024-009548","DOIUrl":"10.1136/jitc-2024-009548","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype characterized by aggressive clinical behavior and poor prognosis. The immune landscape associated with TNBC often reveals high immunogenicity. Therefore, immunotherapy, which has demonstrated its efficacy in different cancer types, could be a promising strategy for TNBC, given the limited therapeutic options currently available besides conventional chemotherapy. The aspartic protease cathepsin D (cath-D) is a tumor cell-associated extracellular protein with protumor activity, a marker of poor prognosis, and a target for antibody-based therapy in TNBC. This commentary provides a synopsis/narrative summary of the development of anti-cath-D antibodies in different formats, their key roles in restoring the antitumor immunity, particularly via activation of tumor-infiltrating natural killer cells, and their dual antitumor effects on cancer cells and stromal cancer-associated fibroblasts, suggesting their interest for clinical use in the light of the current clinical knowledge on TNBC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970832","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":"MAF1 inhibits hepatocarcinogenesis by fostering an immunostimulatory tumor microenvironment.","authors":"Di Cao, Yue-Ning Wang, Chao-Yue Sun, Haojiang Li, Ge Ren, Yu-Feng Zhou, Mei-Yin Zhang, Shuo-Cheng Wang, Shi-Juan Mai, Hui-Yun Wang","doi":"10.1136/jitc-2024-009656","DOIUrl":"10.1136/jitc-2024-009656","url":null,"abstract":"<p><strong>Background: </strong>The biological significance of MAF1, a tumor suppressor, in carcinogenesis and immune response of hepatocellular carcinoma (HCC) remains unreported. Understanding the underlying mechanisms by which MAF1 enhances anti-tumor immunity in HCC is crucial for developing novel immunotherapy strategies and enhancing clinical responses to treatment for patients with HCC.</p><p><strong>Methods: </strong>Mice were subjected to hydrodynamic tail vein injections of transposon vectors to overexpress AKT/NRas, or c-Myc, with or without wild-type (WT) or mutant-activated (-4A) MAF1, or short-hairpin MAF1 (shMAF1). Liver tissues and tumors were harvested and analyzed using histology, immunohistochemistry, immunoblotting, quantitative reverse-transcription PCR, and flow cytometry. MAF1 was overexpressed or knocked down in HCC cells via lentiviral transfection. Cell lines were analyzed using RNA sequencing, immunoblotting, dual luciferase reporter, and chromatin precipitation assays.</p><p><strong>Results: </strong>Both MAF1-WT and MAF1-4A proteins significantly inhibit hepatocarcinogenesis in mice, with the mutant form exhibiting a stronger suppressive effect. Although MAF1 knockdown alone does not induce abnormalities in the mouse liver, it accelerates c-Myc-induced carcinogenesis. Our results provide the first in vivo evidence that MAF1 plays a tumor suppressor role by activating PTEN to suppress the AKT-mammalian target of rapamycin signaling pathway during hepatocarcinogenesis in physiologically relevant tumor models. More importantly, we found that MAF1 not only enhances the intratumoral infiltration of CD8⁺ T cells by increasing CXCL10 secretion but also enhances their functional activity by inhibiting PDL1 transcription in mouse liver cancer, which were confirmed in human HCC or in vitro experiments. Furthermore, PDL1 overexpression accelerates mouse hepatocarcinogenesis by antagonizing the tumor-suppressive role of MAF1.</p><p><strong>Conclusions: </strong>Our study uncovers a novel anti-tumor immunity of MAF1 in hepatocarcinogenesis and human HCC. These findings suggest that the stimulated MAF1 could potentially improve immunotherapy in combination with immune checkpoint inhibitors in HCC patients, especially in those with an absence of T cells in HCC tissues.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970850","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":"Utilization of primary tumor samples for cancer neoantigen discovery.","authors":"Vid Leko, Eric Groh, Shoshana T Levi, Amy R Copeland, Bradley Sinclair White, Billel Gasmi, Yong Li, Victoria Hill, Devikala Gurusamy, Noam Levin, Sanghyun Peter Kim, Sivasish Sindiri, Jared J Gartner, Todd D Prickett, Maria Parkhust, Frank J Lowery, Stephanie L Goff, Steven A Rosenberg, Paul Robbins","doi":"10.1136/jitc-2024-010993","DOIUrl":"10.1136/jitc-2024-010993","url":null,"abstract":"<p><strong>Background: </strong>The use of tumor-infiltrating T lymphocytes (TIL) that recognize cancer neoantigens has led to lasting remissions in metastatic melanoma and certain cases of metastatic epithelial cancer. For the treatment of the latter, selecting cells for therapy typically involves laborious screening of TIL for recognition of autologous tumor-specific mutations, detected through next-generation sequencing of freshly resected metastatic tumors. Our study explored the feasibility of using archived formalin-fixed, paraffin-embedded (FFPE) primary tumor samples for cancer neoantigen discovery, to potentially expedite this process and reduce the need for resections normally required for tumor sequencing.</p><p><strong>Method: </strong>Whole-exome sequencing was conducted on matched primary and metastatic colorectal cancer samples from 22 patients. The distribution of metastatic tumor mutations that were confirmed as neoantigens through cognate TIL screening was evaluated in the corresponding primary tumors. Mutations unique to primary tumors were screened for recognition by metastasis-derived TIL and circulating T lymphocytes.</p><p><strong>Results: </strong>We found that 25 (65.8%) of the 38 validated neoantigens identified in metastatic tumors from 18 patients with colorectal cancer were also present in matched primary tumor samples. This included all 12 neoantigens encoded by putative cancer driver genes, which are generally regarded as superior targets for adoptive cell therapy. The detection rate for other neoantigens, representing mutations without an established role in cancer biology, was 50% (13/26). Gene products encoding neoantigens detected in the primary tumors were not more likely to be clonal or broadly distributed among the analyzed metastatic lesions compared with those undetected in the primary tumors. Additionally, we found that mutations detected only in primary tumor samples did not elicit recognition by metastatic tumor-derived TIL but could elicit specific recognition by the autologous circulating memory T cells.</p><p><strong>Conclusions: </strong>Our findings indicate that primary FFPE tumor-derived screening libraries could be used to discover most neoantigens present in metastatic tumors requiring treatment. Furthermore, this approach can reveal additional neoantigens not present in resected metastatic tumors, prompting further research to understand their clinical relevance as potential therapeutic targets.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970874","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":"Hyperleukocytosis in a neuroblastoma patient after treatment with natural killer T cells expressing a GD2-specific chimeric antigen receptor and IL-15.","authors":"Gengwen Tian, Amy N Courtney, Hangjin Yu, Saleh Bhar, Xin Xu, Gabriel A Barragán, Claudia Martinez Amador, Nisha Ghatwai, Michael S Wood, Deborah Schady, Antonino Montalbano, Shantan Reddy, Aoife M Roche, David de la Cerda, Donald Williams Parsons, Erica J Di Pierro, Frederic D Bushman, Andras Heczey, Leonid S Metelitsa","doi":"10.1136/jitc-2024-010156","DOIUrl":"https://doi.org/10.1136/jitc-2024-010156","url":null,"abstract":"<p><p>The ability of immune cells to expand numerically after infusion distinguishes adoptive immunotherapies from traditional drugs, providing unique therapeutic advantages as well as the potential for unmanageable toxicities. Here, we describe a case of lethal hyperleukocytosis in a patient with neuroblastoma treated on phase 1 clinical trial (NCT03294954) with autologous natural killer T cells (NKTs) expressing a GD2-specific chimeric antigen receptor and cytokine interleukin 15 (GD2-CAR.15). This patient was the first to be treated on dose level (DL) 5 and the first patient whose product was restimulated with K562-derived artificial antigen-presenting cells (aAPCs) instead of autologous peripheral blood mononuclear cells (PBMCs). 12 previously treated patients on DLs 1 through 4 did not experience significant toxicity. Our root-cause analysis revealed no genetic alterations of known clinical significance and excluded the possibility of clonal expansion due to insertional retroviral mutagenesis. We report that the use of aAPCs instead of PBMCs for CAR-NKT restimulation contributed to a hyperproliferative state associated with distinct gene expression that possibly led to explosive lymphocyte expansion and uncontrolled toxicity in the patient. These findings warrant the implementation of measures to control immune cell activation during manufacture of cell therapy products, especially those armed with transgenic cytokines.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970845","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":"HDAC and MEK inhibition synergistically suppresses HOXC6 and enhances PD-1 blockade efficacy in BRAF^V600E-mutant microsatellite stable colorectal cancer.","authors":"Zhuang Sun, Mengyuan Shi, Jinhong Xia, Xin Li, Nan Chen, Hanyang Wang, Zhaoya Gao, Jinying Jia, Peng Yang, Dengbo Ji, Jin Gu","doi":"10.1136/jitc-2024-010460","DOIUrl":"10.1136/jitc-2024-010460","url":null,"abstract":"<p><strong>Background: </strong>B-Raf proto-oncogene, serine/threonine kinase (BRAF)^V600E-mutant microsatellite stable (MSS) colorectal cancer (CRC) constitutes a distinct CRC subgroup, traditionally perceived as minimally responsive to standard therapies. Recent clinical attempts, such as BRAF inhibitors (BRAFi) monotherapy and combining BRAFi with other inhibitors, have yielded unsatisfactory efficacy. This study aims to identify a novel therapeutic strategy for this challenging subgroup.</p><p><strong>Methods: </strong>We first performed a large-scale drug screening using patient-derived organoid models and cell lines to pinpoint potential therapies. Subsequently, we investigated the synergistic effects of identified effective inhibitors and probed their cooperative mechanisms. Concurrently, we explored the immune characteristics of BRAF^V600E MSS CRC using RNA sequencing and multiplex immunohistochemistry. Finally, we established a CT26 BRAF^V637E mouse cell line and validated the efficacy of combining these inhibitors and programmed death 1 (PD-1) blockades in immunocompetent mice.</p><p><strong>Results: </strong>Drug screening identified histone deacetylase (HDAC) inhibitor and mitogen-activated protein kinase kinase (MEK) inhibitor as significantly effective against BRAF^V600E MSS CRC. Further research revealed that these two inhibitors have superior synergistic effects by comprehensively inhibiting the activation of the epidermal growth factor receptor, mitogen-activated protein kinase, and phosphoinositide 3-kinase-protein kinase B pathways and suppressing the key target homeobox C6 (HOXC6). HOXC6, overexpressed in BRAF^V600E MSS CRC, regulates the MYC gene and contributes to treatment resistance, tumor growth, and metastasis. Moreover, the combination therapy demonstrated the ability to enhance antitumor immunity by synergistically upregulating the expression of immune activation-related genes, activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) pathway, and diminishing the tumor cells' DNA mismatch repair capacity. Notably, BRAF^V600E MSS CRC was identified to exhibit a distinct immune microenvironment with increased PD-1⁺ cell infiltration and potential responsiveness to immunotherapy. Echoing the above findings, in vivo, HDAC and MEK inhibitors significantly improved PD-1 blockade efficacy, accompanied by increased CD8⁺ T-cell infiltration.</p><p><strong>Conclusions: </strong>Our findings indicate that combining HDAC inhibitor, MEK inhibitor, and PD-1 blockade is a potential strategy for treating BRAF^V600E-mutant MSS CRC, warranting further investigation in clinical settings.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970839","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":"PD-1 suppresses human CD38⁺ circulating Tfr cells and regulates humoral immunity.","authors":"Heng Zhang, Hui Zheng, Yanchun Wang, Cuncun Chen, Ying Tong, Suhong Xie, Xiaolu Ma, Lin Guo, Renquan Lu","doi":"10.1136/jitc-2024-010026","DOIUrl":"10.1136/jitc-2024-010026","url":null,"abstract":"<p><strong>Background: </strong>Anti-programmed cell death protein 1 (anti-PD-1) antibodies have achieved revolutionary success in cancer therapy. However, the impact of anti-PD-1 therapy on host humoral immunity in humans during cancer immunotherapy requires further investigation.</p><p><strong>Methods: </strong>We evaluated immunoglobulin titers by ELISA and screened the immune landscape of immune cells from 25 healthy donors and 50 cases including 25 new-onset hepatocellular carcinoma (HCC) patients prior to systemic treatment and 25 HCC patients undergoing anti-PD-1 therapy by multicolor flow cytometry. Flow or beads sorted cells were cultured ex vivo for proliferation and functional analysis.</p><p><strong>Results: </strong>Anti-PD-1 therapy significantly increased the levels of IgG and IgA in the periphery of HCC patients. Anti-PD-1 treatment led to an increase in plasmablasts and a notable rise in circulating T follicular regulatory (cTfr) cells, while changes in circulating B cells, T follicular helper cells, or regulatory T cells were not significant. Anti-PD-1 therapy also influenced the proliferation and function of cTfr cells, promoting the differentiation of CD38⁺ cTfr cells. We observed that the CD38⁺ Tfr cell subset in the peripheral blood can promote plasmablast differentiation, associated with altered antibody production.</p><p><strong>Conclusions: </strong>Together, these data demonstrate the immunomodulatory role of PD-1 in restricting the differentiation and function of human cTfr cells and in regulating humoral immunity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970781","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":"Society for Immunotherapy of Cancer: updates and best practices for multiplex immunohistochemistry (IHC) and immunofluorescence (IF) image analysis and data sharing.","authors":"Janis M Taube, Joel C Sunshine, Michael Angelo, Guray Akturk, Margaret Eminizer, Logan L Engle, Cláudia S Ferreira, Sacha Gnjatic, Benjamin Green, Shirley Greenbaum, Noah F Greenwald, Cyrus V Hedvat, Travis J Hollmann, Daniel Jiménez-Sánchez, Konstanty Korski, Ana Lako, Edwin R Parra, Marlon C Rebelatto, David L Rimm, Scott J Rodig, Jamie Rodriguez-Canales, Jeffrey S Roskes, Kurt A Schalper, Emanuel Schenck, Keith E Steele, Michael J Surace, Alexander S Szalay, Michael T Tetzlaff, Ignacio I Wistuba, Jennifer H Yearley, Carlo B Bifulco","doi":"10.1136/jitc-2024-008875","DOIUrl":"10.1136/jitc-2024-008875","url":null,"abstract":"<p><strong>Objectives: </strong>Multiplex immunohistochemistry and immunofluorescence (mIHC/IF) are emerging technologies that can be used to help define complex immunophenotypes in tissue, quantify immune cell subsets, and assess the spatial arrangement of marker expression. mIHC/IF assays require concerted efforts to optimize and validate the multiplex staining protocols prior to their application on slides. The best practice guidelines for staining and validation of mIHC/IF assays across platforms were previously published by this task force. The current effort represents a complementary manuscript for mIHC/IF analysis focused on the associated image analysis and data management.</p><p><strong>Methods: </strong>The Society for Immunotherapy of Cancer convened a task force of pathologists and laboratory leaders from academic centers as well as experts from pharmaceutical and diagnostic companies to develop best practice guidelines for the quantitative image analysis of mIHC/IF output and data management considerations.</p><p><strong>Results: </strong>Best-practice approaches for image acquisition, color deconvolution and spectral unmixing, tissue and cell segmentation, phenotyping, and algorithm verification are reviewed. Additional quality control (QC) measures such as batch-to-batch correction and QC for assembled images are also discussed. Recommendations for sharing raw outputs, processed results, key analysis programs and source code, and representative photomicrographs from mIHC/IF assays are included. Lastly, multi-institutional harmonization efforts are described.</p><p><strong>Conclusions: </strong>mIHC/IF technologies are maturing and are routinely included in research studies and moving towards clinical use. Guidelines for how to perform and standardize image analysis on mIHC/IF-stained slides will likely contribute to more comparable results across laboratories and pave the way for clinical implementation. A checklist encompassing these two-part guidelines for the generation of robust data from quantitative mIHC/IF assays will be provided in a third publication from this task force. While the current effort is mainly focused on best practices for characterizing the tumor microenvironment, these principles are broadly applicable to any mIHC/IF assay and associated image analysis.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949218","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":"Differential impact of TIM-3 ligands on NK cell function.","authors":"Juncheng Wang, Housaiyin Li, Aditi Kulkarni, Jennifer L Anderson, Pragati Upadhyay, Onyedikachi Victor Onyekachi, Lidia M R B Arantes, Hridesh Banerjee, Lawrence P Kane, Xin Zhang, Tullia C Bruno, Riyue Bao, Robert L Ferris, Lazar Vujanovic","doi":"10.1136/jitc-2024-010618","DOIUrl":"10.1136/jitc-2024-010618","url":null,"abstract":"<p><strong>Background: </strong>The transmembrane protein T-cell immunoglobulin and mucin-domain containing molecule 3 (TIM-3) is an immune checkpoint receptor that is expressed by a variety of leukocyte subsets, particularly in the tumor microenvironment. An effective TIM-3-targeting therapy should account for multiple biological factors, including the disease setting, the specific cell types involved and their varying sensitivities to the four putative TIM-3 ligands (galectin-9, phosphatidylserine, high mobility group protein B1 and carcinoembryonic antigen cell adhesion molecule 1), each of which engages a unique binding site on the receptor's variable immunoglobulin domain. The primary objectives of this study were to assess the prevalence and function of TIM-3⁺ natural killer (NK) cells in patients with head and neck squamous cell carcinoma (HNSCC), determine whether the four TIM-3 ligands differentially affect TIM-3⁺ NK cell functions, identify the most immunosuppressive ligand, and evaluate whether targeting ligand-mediated TIM-3 signaling enhances NK cell effector functions.</p><p><strong>Methods: </strong>Single-cell RNA sequencing and flow cytometry were used to study the prevalence, phenotypes and function of TIM-3⁺ NK cells in HNSCC patient tumors and blood. In vitro killing, proliferation and cytokine production assays were implemented to evaluate whether the four TIM-3 ligands differentially modulate TIM-3⁺ NK cell functions, and whether disruption of TIM-3/ligand interaction can enhance NK cell-mediated antitumor effector mechanisms. Finally, The Cancer Genome Atlas survival analysis and digital spatial profiling were employed to study the potential impact of etiology-associated differences on patients with HNSCC outcomes.</p><p><strong>Results: </strong>We demonstrate that TIM-3 is highly prevalent on circulating and tumor-infiltrating NK cells. It co-expresses with CD44 and marks NK cells with heightened effector potential. Among the four putative TIM-3 ligands, galectin-9 most consistently suppresses NK cell-mediated cytotoxicity and proliferation through TIM-3 and CD44 signaling, respectively, but promotes IFN-γ release in a TIM-3-dependent manner. Among patients with HNSCC, an elevated intratumoral TIM-3⁺ NK cell gene signature associates with worse outcomes, specifically in those with human papillomavirus (HPV)⁺ disease, potentially attributable to higher galectin-9 levels in HPV⁺ versus HPV^- patients.</p><p><strong>Conclusions: </strong>Our findings underscore the complex functional impact of TIM-3 ligand signaling, which is consistent with recent clinical trials suggesting that targeting TIM-3 alone is suboptimal as an immunotherapeutic approach for treating malignancies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949195","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":"Targeting the NLRP3 inflammasome abrogates cardiotoxicity of immune checkpoint blockers.","authors":"Yang Lu, Jiamin Gao, Yachen Hou, Han Yang, Dashuai Wang, Ge Zhang, Zhen Qin, Pengchong Du, Zhenwei Wang, Yunzhe Wang, Quanzhou Chen, Zhaowei Sun, Ping Li, Jinying Zhang, Junnan Tang","doi":"10.1136/jitc-2024-010127","DOIUrl":"10.1136/jitc-2024-010127","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many malignant tumors. However, ICI-induced hyper-immune activation causes cardiotoxicity. Traditional treatments such as glucocorticoids and immunosuppressants have limited effectiveness and may even accelerate tumor growth. This study aimed to identify approaches that effectively reduce cardiotoxicity and simultaneously preserve or enhance the antitumor immunity of ICI therapy.</p><p><strong>Methods: </strong>ICI injection in melanoma-bearing C57BL/6J female mice was used to simulate cardiotoxicity in patients with tumor undergoing immune therapy. MCC950 was used to block nod-like receptor protein 3 (NLRP3) inflammasome activity. Echocardiography, immunofluorescence, flow cytometry, and reverse transcription quantitative polymerase chain reaction were used to assess cardiac function, immune cell populations, and inflammatory factor levels. Bulk and single-cell RNA sequencing was used to detect the changes in cardiac transcriptome and immunological network.</p><p><strong>Results: </strong>NLRP3 inhibition reduced inflammatory response and improved cardiac function. Notably, NLRP3 inhibition also resulted in a pronounced suppression of tumor growth. Single-cell RNA sequencing elucidated that MCC950 treatment reduced the cardiac infiltration of pathogenic macrophages, cytotoxic T cells, activated T cells, and their production of inflammatory cytokines, while enhancing the presence of reparative macrophages and naive T cells. In addition, MCC950 attenuated cardiotoxicity induced by dual programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immunotherapy and promoted tumor regression, and showed efficacy in treating established cardiotoxicity.</p><p><strong>Conclusions: </strong>Our findings provide a promising clinical approach for preventing and treating cardiotoxicity induced by ICIs, dissociating the antitumor efficacy of ICI-based therapies from their cardiotoxic side effects.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949221","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":"Disruption of tumor-intrinsic PGAM5 increases anti-PD-1 efficacy through the CCL2 signaling pathway.","authors":"Xiaoying Wei, Hong Wang, Huiquan Liu, Jianguo Wang, Peijie Zhou, Xiaoyang Li, Yuan He, Yan Li, Dong Han, Ting Mei, Yuwen Wang, Ziye Li, Junhao Ning, Zilong Xu, Anlin Wang, Yixuan Li, Jingjing Cheng, Dong Qian","doi":"10.1136/jitc-2024-009993","DOIUrl":"10.1136/jitc-2024-009993","url":null,"abstract":"<p><strong>Background: </strong>Immunosuppressive phenotype compromised immunotherapy efficacy of hepatocellular carcinoma. Tumor cells intrinsic mitochondria dynamics could pass effects on the extracellular microenvironment through mtDNA stress. PGAM5 anchors at mitochondria and regulates mitochondria functions. We aim to explore whether the regulation of tumor-intrinsic PGAM5 on mitochondria affects tumor-infiltrating immune cells in the microenvironment and whether tumor-intrinsic PGAM5 can be a therapeutic target to enhance the immunotherapy efficacy of hepatocellular carcinoma (HCC).</p><p><strong>Methods: </strong>We analyzed the correlation of PGAM5 expression and immune cells infiltration using Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) data sets based on cibersort algorithm and tumor-tissue arrays from two independent cohorts. To further validate our findings, we established subcutaneous and orthotopic mouse HCC models with tumor-intrinsic Pgam5 deficiency and analyzed tumor-infiltrating immune cells by flow cytometry and single-cell RNA sequencing. Mechanistically, we established an in vitro co-culture system and analyzed proteomics data to find out the bridge between tumor cell PGAM5 and tumor-associated macrophages (TAMs) in the microenvironment. Immunofluorescence, chromatin-immunoprecipitation, ELISA, mass spectrometry were conducted to explore the molecular pathway. Macrophages were depleted to investigate whether the effects of tumor-intrinsic PGAM5 on TAMs could affect immunotherapy efficacy in HCC orthotopic and subcutaneous mouse models.</p><p><strong>Results: </strong>PGAM5 expression in tumor was positively correlated with M2-phenotype TAM infiltration in patients with both HCC and mouse HCC tumor models. High tumor-intrinsic PGAM5 expression promoting M2 TAMs infiltration correlated with poor clinical-pathological characteristics and prognosis in patients with HCC. Disruption of tumor-intrinsic Pgam5 reduced TAM M2 polarization and inhibited HCC tumor growth in tumor-bearing mice. Mechanistically, in HCC cells PGAM5 deficiency inhibited mitochondria fission by promoting TRIM28 binding with DRP1, which increased ubiquitination and degradation of DRP1. Tumor-intrinsic PGAM5 deficiency mediated mitochondria fusion and reduced cytosolic mtDNA stress which attenuated TLR9 activation and downstream NF-κB-regulated CCL2 secretion. Furthermore, disruption of tumor-intrinsic Pgam5 significantly facilitated CD8⁺ T cells activation and improved anti-programmed cell death protein-1 therapeutic efficacy with macrophages depletion compromising synergistic antitumor immune response.</p><p><strong>Conclusion: </strong>Our results shed light on the effect of tumor mitochondria dynamics on TAMs in tumor microenvironment. Tumor-intrinsic PGAM5 can be a therapeutic target to improve immunotherapy efficacy in patients with HCC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949198","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}