Journal for Immunotherapy of Cancer最新文献

{"title":"SIGLEC11 promotes M2 macrophage polarization through AKT-mTOR signaling and facilitates the progression of gastric cancer.","authors":"Jingxin Yin, Yang Lu, Yihao Liu, Qimeng Shi, Minmin Shi, Zhenggang Zhu, Da Fu, Zhenqiang Wang, Chen Li","doi":"10.1136/jitc-2024-010162","DOIUrl":"https://doi.org/10.1136/jitc-2024-010162","url":null,"abstract":"<p><strong>Background: </strong>Sialic acid-binding immunoglobulin-like lectins (SIGLECs) are widely expressed on immune cell surfaces, play an important role in maintaining immune homeostasis and regulating inflammatory responses, and are increasingly emerging as potential targets for tumor immunotherapy. However, the expression profile and crucial role of SIGLEC11 in gastric cancer (GC) remain unclear. This study aimed to elucidate the prognostic relevance of SIGLEC11 expression and its role in the immune microenvironment in patients with GC.</p><p><strong>Methods: </strong>SIGLEC11 expression profile was analyzed using bioinformatics, immunohistochemistry, and immunofluorescence staining. Flow cytometry, mouse tumor models, patient-derived tumor organoid models, and RNA sequencing were used to explore the potential functions with the underlying mechanisms of SIGLEC11 in a coculture system of macrophages and GC cells.</p><p><strong>Results: </strong>We demonstrated that SIGLEC11 was predominantly expressed in normal tissues. However, tumor-infiltrating SIGLEC11⁺ cells in the high SIGLEC11 expression subgroups showed poor overall survival, which was associated with the expression of an immunosuppressive regulator. Our results showed that SIGLEC11 was predominantly expressed in monocytes and macrophages and selectively upregulated in tumor-associated macrophages. Furthermore, SIGLEC11 promoted macrophage M2 polarization via AKT-mTOR signaling. In addition, SIGLEC11⁺ macrophages accelerate GC progression.</p><p><strong>Conclusions: </strong>The abundance of SIGLEC11⁺ M2-like macrophage-infiltrating tumors may serve as a biomarker for identifying immunosuppressive subtypes of GC. Thus, the potential role of SIGLEC11⁺ M2 macrophages as therapeutic targets warrants further investigation.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927110","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":"Early treatment discontinuation in patients with deficient mismatch repair or microsatellite instability high metastatic colorectal cancer receiving immune checkpoint inhibitors.","authors":"Julien Taieb, Margherita Ambrosini, Emily Alouani, Sara Lonardi, Frank A Sinicrope, Marie Decraecker, Alice Boileve, Emilie Hafliger, Thibault Mazard, Simon Pernot, Pauline Parent, Javier Ros, Michael J Overman, Priya Jayachandran, Vincenzo Nasca, Lisa Salvatore, Rosine Guimbaud, Chiara Cremolini, David Tougeron, Filippo Pietrantonio","doi":"10.1136/jitc-2024-010424","DOIUrl":"https://doi.org/10.1136/jitc-2024-010424","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD).</p><p><strong>Methods: </strong>To assess whether ETD is associated with similar outcomes compared with LTD, we assembled an international cohort of patients with dMMR/MSI-H mCRC treated with ICIs who stopped treatment for a reason other than PD within 395 days (ETD group) and compared them to those who continued for >395 days (LTD group). Outcomes were adjusted for patient/tumor characteristics. Primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), overall survival (OS) and safety.</p><p><strong>Results: </strong>Of 976 patients, 137 and 394 were allocated to the ETD and LTD groups, respectively. In the ETD group, treatment was discontinued due to toxicity (n=56), objective response (n=43), surgery (n=28), patient decision (n=2) or other reasons (n=8). Baseline characteristics were well balanced between the two groups: 22% in both groups received both anti-programmed death-(ligand) 1 (anti-PD-(L)1) + anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4); all others received anti-PD-(L)1 monotherapy. ORR to ICIs was 81% in both groups. Median duration of treatment was ~7 months in the ETD and ~24 months in the LTD group. After a median follow-up of 44 months (IQR: 30-67), similar PFS (HR: 0.92, 95% CI: 0.60 to 1.40, p=0.69) and OS (HR: 1.15, 95% CI: 0.66 to 1.99, p=0.62) from the start of ICIs were observed in ETD and LTD patients. In the ETD group, 28 (20%) patients had a PFS event and 9 restarted ICIs with a disease control rate of 66%.</p><p><strong>Conclusions: </strong>In our international series of dMMR/MSI-H mCRC, ETD of ICIs in the absence of PD did not seem detrimental in terms of PFS and OS compared with continuing treatment beyond 1 year. Randomized clinical trials to compare short and long treatment duration are now warranted.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927105","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":"Effect of radiotherapy exposure on fruquintinib plus sintilimab treatment in refractory microsatellite stable metastatic colorectal cancer: a prospective observation study.","authors":"Mingxia Cheng, Min Jin, Shengli Yang, Lei Zhao, Dandan Yu, Zhenyu Lin, Pindong Li, Chuying Huang, Junli Liu, Jing Wang, Jun Xue, Hong Ma, Jianli Hu, Kunyu Yang, Tao Zhang, Hongli Liu","doi":"10.1136/jitc-2024-009415","DOIUrl":"https://doi.org/10.1136/jitc-2024-009415","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) in combination with antiangiogenic drugs have shown promising outcomes in the third-line and subsequent treatments of patients with microsatellite stable metastatic colorectal cancer (MSS-mCRC). Radiotherapy (RT) may enhance the antitumor effect of immunotherapy. However, the effect of RT exposure on patients receiving ICIs and targeted therapy remains unclear. This study aimed to investigate the association between RT exposure and clinical responses to fruquintinib (a highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor) plus sintilimab (an anti-programmed death 1 antibody; F&S) in previously treated patients with MSS-mCRC and to explore predictive biomarkers.</p><p><strong>Methods: </strong>In this prospective observational study, patients with mCRC receiving F&S as third-line or subsequent treatment were enrolled. Eligible patients were divided into the RT cohort (RTC) and the non-RT cohort (NRTC) according to their RT history. The primary endpoint was the objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Pretreatment fecal and serum samples were collected for microbiome analysis, metabolome analysis, and immune signatures to identify biomarkers for treatment.</p><p><strong>Results: </strong>A total of 55 patients were included, of which 25 were in the RTC and 30 in the NRTC. Better ORR (28.0% vs 6.7%, p=0.048), DCR (80.0% vs 36.7%, p=0.002), median PFS (6.2 vs 2.7 months, p<0.001), and median OS (14.8 vs 5.9 months, p=0.019) were noted in patients with RTC than those with NRTC. The enrichment of <i>Lactobacillus</i>, <i>Bifidobacterium</i>, and PC(20:5(5Z,8Z,11Z,14Z,17Z)/20:3(8Z,11Z,14Z)) in RTC significantly predicted better DCR and PFS, whereas guanosine and interleukin-10 predominated in patients with NRTC were negatively correlated with PFS and OS.</p><p><strong>Conclusions: </strong>Patients with RT exposure benefited significantly from F&S in the third-line or subsequent treatment for MSS-mCRC. Gut microbiota, metabolites, and cytokines may help predict F&S outcomes for mCRC, which may be helpful in treatment decision-making.</p><p><strong>Trial registration number: </strong>ClinicalTrials.gov identifier: NCT05635149.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927107","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":"Depletion of myeloid-derived suppressor cells sensitizes murine multiple myeloma to PD-1 checkpoint inhibitors.","authors":"Wei Xiong, Liuling Xiao, Rui Duan, Qiang Wang, Miao Xian, Chuanchao Zhang, Pan Su, Yabo Li, Ling Zhong, Jianfei Qian, Chengyun Zheng, Qing Yi","doi":"10.1136/jitc-2024-008979","DOIUrl":"https://doi.org/10.1136/jitc-2024-008979","url":null,"abstract":"<p><strong>Background: </strong>Cancer immunotherapy using immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, patients with multiple myeloma (MM) rarely respond to ICB. Accumulating evidence indicates that the complicated tumor microenvironment (TME) significantly impacts the efficacy of ICB therapy. Therefore, investigating how TME components in MM influence ICB treatment is urgent.</p><p><strong>Methods: </strong>We employed two well-established murine myeloma models, 5TGM1 and Vk*MYC, by intravenously injecting 5TGM1 or Vk*MYC cells into mice, respectively, to determine ICB therapeutic efficacy in MM. Total mouse IgG or Ig2b ELISA or QuickGel split beta SPE kits and in vivo bioluminescent imaging were used to monitor MM tumor burden. Cytometry by time of flight (CyTOF) was used to quantify MM TME components. T cell proliferation and function were detected using flow cytometry. Peptide-Fc fusion proteins were used to deplete myeloid-derived suppressor cells (MDSCs). MM^DTR, Foxp3^DTR, CD4 KO and CD8 KO mice were used to elucidate the underlying mechanisms. Gene expression levels in human MM were analyzed using Gene Expression Omnibus public datasets.</p><p><strong>Results: </strong>We found that programmed cell death protein 1 (PD-1) antibody treatment had a therapeutic effect in 5TGM1 mice; it was ineffective in Vk*MYC mice. CyTOF indicated that the bone marrow (BM) of both models was inflamed, suggesting that immune suppressive cells might be inhibiting the reactivation of T cells in the BM. We observed higher numbers of MDSCs, regulatory T (Treg) cells, and tumor-associated macrophage (TAMs) in myeloma BM compared with that of tumor-free mice. Specifically, depleting MDSCs, but not Treg cells or TAMs, sensitized Vk*MYC mice and enhanced the response of 5TGM1 mice to PD-1 ICB, which was dependent on CD8⁺ but not CD4⁺ T cells. MDSCs, especially M-MDSCs and CD84⁺ MDSCs, significantly inhibited the activation and cytotoxic cytokine production of CD8⁺ T cells in vitro. Moreover, database profiling of patient BM revealed a negative correlation between MDSCs signature genes and cytotoxic CD8⁺ T cell signature genes, with post-maintenance patients with myeloma displaying a higher ratio of cytotoxic CD8⁺ T cell to MDSCs signature genes compared with pretreated patients.</p><p><strong>Conclusion: </strong>Our study highlights the potential of MDSCs depletion in enhancing the sensitivity of patients with myeloma to PD-1 ICB therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927102","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":"Targeting Siglec-E facilitates tumor vaccine-induced antitumor immunity in renal carcinoma.","authors":"Yanyan Zheng, Jiawei Wang, Guangya Zhao, Zichun Zhang, Yingxiang Shao, Bowen Lu, Yuchen Zhang, Renjin Chen, Li Sun, Xiaohui Xie, Jiage Ding, Junnian Zheng, Dafei Chai","doi":"10.1136/jitc-2024-010521","DOIUrl":"https://doi.org/10.1136/jitc-2024-010521","url":null,"abstract":"<p><strong>Background: </strong>Siglec-E is an immune checkpoint inhibitory molecule. Expression of Siglec-E on the immune cells has been shown to promote tumor regression. This study aimed to develop an adenovirus (Ad) vaccine targeting Siglec-E and carbonic anhydrase IX (CAIX) (Ad-Siglec-E/CAIX) and to evaluate its potential antitumor effects in several preclinical renal cancer models.</p><p><strong>Methods: </strong>Ad vaccines encoding Siglec-E or CAIX were developed and evaluated for their therapeutic potential in mouse subcutaneous, lung metastatic, and orthotopic tumor models. The expression of Ad-Siglec-E/CAIX was confirmed via PCR and flow cytometry. Immune responses induced by Ad-Siglec-E/CAIX were assessed in vitro and in vivo using flow cytometry, immunohistochemistry, ELISA, histological analysis, cell proliferation, enzyme-linked immunosorbent spot, cytotoxic T lymphocytes (CTL) killing, and cell depletion assays.</p><p><strong>Results: </strong>Ad-Siglec-E/CAIX vaccine induced the increase of tumor-infiltrated immune cells, and significantly suppressed the subcutaneous tumor growth of renal carcinoma. Immunization with Ad-Siglec-E/CAIX promoted the induction and maturation of CD11c⁺ dendritic cells and their subsets, which in turn enhanced tumor-specific CD8⁺ T cell immune responses, as evidenced by increased CD8⁺ T cell proliferation and CTL activity. Importantly, the deletion of CD8⁺ T cells in vivo abolished the antitumor effect of the Ad-Siglec-E/CAIX vaccine, highlighting the essential role of functional CD8⁺ T cell responses. The potent therapeutic efficacy of the Ad-Siglec-E/CAIX vaccine was also observed in lung metastasis and orthotopic tumor models through tumor-specific CD8⁺ T cell immune responses.</p><p><strong>Conclusions: </strong>Our results indicate that targeting Siglec-E enhances the therapeutic efficacy of Ad-CAIX against renal carcinoma, providing a promising therapeutic option for solid tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927114","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":"Spatial and single-cell transcriptomics reveal cellular heterogeneity and a novel cancer-promoting Treg cell subset in human clear-cell renal cell carcinoma.","authors":"Xiyu Song, Yumeng Zhu, Wenwen Geng, Jianhua Jiao, Hongjiao Liu, Ruo Chen, Qian He, Lijuan Wang, Xiuxuan Sun, Weijun Qin, Jiejie Geng, Zhinan Chen","doi":"10.1136/jitc-2024-010183","DOIUrl":"https://doi.org/10.1136/jitc-2024-010183","url":null,"abstract":"<p><strong>Background: </strong>Clear cell renal cell carcinoma (ccRCC) is the most common histologic type of RCC. However, the spatial and functional heterogeneity of immunosuppressive cells and the mechanisms by which their interactions promote immunosuppression in the ccRCC have not been thoroughly investigated.</p><p><strong>Methods: </strong>To further investigate the cellular and regional heterogeneity of ccRCC, we analyzed single-cell and spatial transcriptome RNA sequencing data from four patients, which were obtained from samples from multiple regions, including the tumor core, tumor-normal interface, and distal normal tissue. On the basis, the findings were investigated in vitro using tissue and blood samples from 15 patients with ccRCC and validated in the broader samples on tissue microarrays.</p><p><strong>Results: </strong>In this study, we revealed previously unreported subsets of both stromal and immune cells, as well as mapped their spatial location at finer resolution. In addition, we validated the clusters of tumor cells after removing batch effects according to six characterized gene sets, including epithelial-mesenchymal transition^high clusters, metastatic clusters and proximal tubule^high clusters. Importantly, we identified a special regulatory T (Treg) cell subpopulation that has the molecular characteristics of terminal effector Treg cells but expresses multiple cytokines, such as interleukin (IL)-1β and IL-18. This group of Treg cells has stronger immunosuppressive function and was associated with a worse prognosis in ccRCC cohorts. They were colocalized with <i>MRC1</i> ⁺ <i>FOLR2</i> ⁺ tumor-associated macrophages (TAMs) at the tumor-normal interface to form a positive feedback loop, maintaining a synergistic procarcinogenic effect. In addition, we traced the origin of IL-1β⁺ Treg cells and revealed that IL-18 can induce the expression of IL-1β in Treg cells via the ERK/NF-κB pathway.</p><p><strong>Conclusions: </strong>We demonstrated a novel cancer-promoting Treg cell subset and its interactions with <i>MRC1</i> ⁺ <i>FOLR2</i> ⁺TAMs, which provides new insight into Treg cell heterogeneity and potential therapeutic targets for ccRCC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927112","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":"Correction: Associations of concomitant medications with immune-related adverse events and survival in advanced cancers treated with immune checkpoint inhibitors: a comprehensive pan-cancer analysis.","authors":"","doi":"10.1136/jitc-2024-008806corr1","DOIUrl":"https://doi.org/10.1136/jitc-2024-008806corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 12","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909544","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":"Neoadjuvant atezolizumab + chemotherapy for resectable NSCLC: 3-year clinical update of phase II clinical trial results and translational findings.","authors":"Brian S Henick, Peter D Koch, Justin F Gainor, Mark M Awad, Codruta Chiuzan, Stephanie Izard, Yohanna Georgis, Samyukta Mallick, Robert F Garofano, Cheryl V Wong, Anjali Saqi, Jessica Grindheim, Katja Schulze, Joshua R Sonett, Naiyer A Rizvi, Benjamin Izar, Alison M Taylor, Catherine A Shu","doi":"10.1136/jitc-2024-009301","DOIUrl":"https://doi.org/10.1136/jitc-2024-009301","url":null,"abstract":"<p><strong>Introduction: </strong>Neoadjuvant chemoimmunotherapy has achieved overall survival (OS) benefit for patients with resectable non-small cell lung cancer (NSCLC). Here, we present outcomes after 3 years of follow-up from the first reported study of neoadjuvant atezolizumab+chemotherapy.</p><p><strong>Methods: </strong>This open-label, multicenter single-arm investigator-initiated phase II study conducted at three US hospitals tested up to four cycles of atezolizumab, carboplatin, and nab-paclitaxel prior to surgery. Major pathological response (MPR, primary endpoint) was previously reported; here, we report 3-year disease-free survival (DFS), OS, and clinical characteristics of patients developing brain metastases (BM) with integrated data from tumor genomics, gene expression, and quantitative immunofluorescent measurement of immune markers.</p><p><strong>Results: </strong>Of 30 enrolled patients, 29 were taken to the operating room. 26 underwent R0 resection, with 17 experiencing MPR (10 pCR). With a median follow-up of 39.5 months, the median OS was 55.8 months, and the median DFS was 34.5 months. Landmark OS at 36 months was 77%. Among 14 patients with recurrent disease, 6 patients had BM. Patients whose tumors had mutations in <i>STK11</i> and <i>KEAP1</i> did not have a significantly higher incidence of BM. Reduced copy number of <i>STK11</i> and <i>KEAP1</i>, both residing on chromosome 19p, was observed in ~1/3 of tumors. Reduced CN of <i>STK11</i> was significantly associated with worse pathological response and incidence of BM.</p><p><strong>Conclusions: </strong>Consistent with recent phase III studies, 3-year OS data with neoadjuvant atezolizumab+chemotherapy was associated with prolonged PFS and OS. Establishing associations between <i>STK11</i> and <i>KEAP1</i> genomic alterations and key clinical outcomes in early-stage NSCLC requires further study.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 12","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894412","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":"Lactylation-driven TNFR2 expression in regulatory T cells promotes the progression of malignant pleural effusion.","authors":"Qianqian Xue, Wenbei Peng, Siyu Zhang, Xiaoshan Wei, Linlin Ye, Zihao Wang, Xuan Xiang, Yao Liu, Haolei Wang, Qiong Zhou","doi":"10.1136/jitc-2024-010040","DOIUrl":"10.1136/jitc-2024-010040","url":null,"abstract":"<p><strong>Background: </strong>Although tumor necrosis factor receptor 2 (TNFR2) has been recognized as an attractive next-generation candidate target for cancer immunotherapy, the factors that regulate the gene expression and their mechanistic effects on tumor-infiltrating regulatory T cells (Treg cells) remain poorly understood.</p><p><strong>Methods: </strong>Single-cell RNA sequencing analysis was employed to analyze the phenotypic and functional differences between TNFR2⁺ Treg cells and TNFR2^- Treg cells. Malignant pleural effusion (MPE) from humans and mouse was used to investigate the potential mechanisms by which lactate regulates TNFR2 expression.</p><p><strong>Results: </strong>Treg cells with high TNFR2 expression exhibited elevated levels of immune checkpoint molecules. Additionally, the high expression of TNFR2 on Treg cells was positively correlated with a poor prognosis in MPE patients. Moreover, we revealed that lactate upregulated TNFR2 expression on Treg cells, thereby enhancing their immunosuppressive function in MPE. Mechanistically, lactate modulated the gene transcription of transcription factor nuclear factor-κB p65 (NF-κB p65) through histone H3K18 lactylation (H3K18la), subsequently upregulating the gene expression of TNFR2 and expediting the progression of MPE. Notably, lactate metabolism blockade combined with immune checkpoint blockade (ICB) therapy effectively enhanced the efficacy of ICB therapy, prolonged the survival time of MPE mice, and improved immunosuppression in the microenvironment of MPE.</p><p><strong>Conclusions: </strong>The study explains the mechanism that regulates TNFR2 expression on Treg cells and its function in MPE progression, providing novel insights into the epigenetic regulation of tumor development and metabolic strategies for MPE treatment by targeting lactate metabolism in Treg cells.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 12","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11683941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894411","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":"High peripheral T cell diversity is associated with lower risk of toxicity and superior response to dual immune checkpoint inhibitor therapy in patients with metastatic NSCLC.","authors":"Mehmet Altan, Ruoxing Li, Ziyi Li, Runzhe Chen, Ajay Sheshadri, Hai T Tran, Latasha Little, Joshua Baguley, Jefferson Sinson, Natalie Vokes, Saumil Gandhi, Mara B Antonoff, Stephen G Swisher, Greg Lizee, Alexandre Reuben, John V Heymach, Jianjun Zhang","doi":"10.1136/jitc-2024-008950","DOIUrl":"10.1136/jitc-2024-008950","url":null,"abstract":"<p><strong>Introduction: </strong>Despite significant successes, immune checkpoint blockade fails to achieve clinical responses in a significant proportion of patients, predictive markers for responses are imperfect and immune-related adverse events (irAEs) are unpredictable. We used T-cell receptor (TCR) sequencing to systematically analyze prospectively collected patient blood samples from a randomized clinical trial of dual immune checkpoint inhibitor therapy to evaluate changes in the T-cell repertoire and their association with response and irAEs.</p><p><strong>Methods: </strong>Patients with immunotherapy-naïve metastatic non-small cell lung cancer (NSCLC) were treated with ipilimumab and nivolumab according to trial protocol (LONESTAR, NCT03391869). Blood samples were systematically obtained at baseline (n=107), after 12 weeks of ipilimumab and nivolumab (n=91), and at the time of grade ≥2 irAEs (n=77). For analysis of T-cell repertoire, we performed immunoSEQ to assess the complementary determining region 3β region of the TCR involved in antigen binding.</p><p><strong>Results: </strong>A total of 250 samples from 119 patients were analyzed. Patients who had a response to therapy exhibited greater T-cell diversity at baseline. Interestingly, patients with irAEs demonstrated lower T-cell richness at the time of toxicity compared with those without irAEs.</p><p><strong>Conclusion: </strong>Our study highlights the potential impact of peripheral blood T-cell repertoire on clinical response and toxicities from the combination of ipilimumab and nivolumab in patients with metastatic NSCLC. These findings suggest that analysis of peripheral blood T-cell repertoire may help to guide patient selection for treatment with ipilimumab and nivolumab.</p><p><strong>Trial registration number: </strong>NCT03391869.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 12","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11683914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894406","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}