Cancer Immunology, Immunotherapy最新文献

{"title":"NSUN2/ALYREF axis-driven m⁵C methylation enhances PD-L1 expression and facilitates immune evasion in non-small-cell lung cancer.","authors":"Yiran Yang, Leiqun Cao, Xin Xu, Dan Li, Yiran Deng, Lan Li, Bingjie Zeng, Haixia Jiang, Liang Shan, Yiwen Huang, Yunhua Xu, Lifang Ma","doi":"10.1007/s00262-025-03986-5","DOIUrl":"10.1007/s00262-025-03986-5","url":null,"abstract":"<p><p>Non-small-cell lung cancer (NSCLC) represents a highly prevalent form of malignancy. 5-methylcytosine (m⁵C) methylation functions as a key post-transcriptional regulatory mechanism linked to cancer progression. The persistent expression of PD-L1 in tumor cells plays a pivotal role in facilitating immune evasion and promoting T-cell exhaustion. However, the involvement of m⁵C in NSCLC immune evasion remains inadequately understood. This study seeks to explore the function of the m⁵C methyltransferase NSUN2 in modulating PD-L1 expression and facilitating immune evasion in NSCLC. Our findings indicate elevated levels of NSUN2 and ALYREF in NSCLC, and both promote the growth of NSCLC cells and the progression of lung cancer. Moreover, the expression of PD-L1 in NSCLC tissues positively correlates with NSUN2 and ALYREF expression. We then discovered that PD-L1 acts as a downstream target of NSUN2-mediated m⁵C modification in NSCLC cells. Knocking down NSUN2 significantly reduces m⁵C modification of PD-L1 mRNA, thereby decreasing its stability via the m⁵C reader ALYREF-dependent manner. Furthermore, inhibiting NSUN2 enhanced CD8⁺ T-cell activation and infiltration mediated by PD-L1, thereby boosting antitumor immunity, as confirmed in both in vitro and in vivo experiments. Collectively, these results suggested that NSUN2/ALYREF/PD-L1 axis plays a critical role in promoting NSCLC progression and tumor cell immune suppression, highlighting its potential as a novel therapeutic strategy for NSCLC immunotherapy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 4","pages":"132"},"PeriodicalIF":4.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540274","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":"Single-cell transcriptome sequencing reveals the immune microenvironment in bronchoalveolar lavage fluid of checkpoint inhibitor-related pneumonitis.","authors":"Linpeng Zheng, Fenglin Lin, Dingqin Cai, Longyao Zhang, Chenrui Yin, Yaxian Qi, Lingyou Sun, Lingchen Li, Xiewan Chen, Jianbo Zhu, Jianguo Sun","doi":"10.1007/s00262-025-03983-8","DOIUrl":"10.1007/s00262-025-03983-8","url":null,"abstract":"<p><strong>Background and objectives: </strong>Immune checkpoint inhibitors (ICIs) bring cancer patients tumor control and survival benefits, yet they also trigger immune-related adverse effects (irAEs), notably checkpoint inhibitor-related pneumonitis (CIP), affecting about 5% of patients among whom 1-2% experiencing severe grade 3 or higher pneumonitis. Current research points to potential links with T cell subset dysfunction and autoantibody increase, but the specific mechanisms underlying different grades of CIP are understudied.</p><p><strong>Methods: </strong>Herein, we employed single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid (BALF) from CIP patients across varying severity levels, aiming to elucidate underlying immune environment and mechanisms of CIP progression at cellular and molecular levels.</p><p><strong>Findings: </strong>Totally, 121,409 high qualified cells from BALF of 11 patients were annotated and categorized into five major cell types. Severe CIP (CIP-S) cases have a significant increase in the percentage of unreported epithelial cells in their bronchoalveolar lavage fluid compared with mild CIP (CIP-M) cases. These cells were defined as aberrant basaloid cells. They upregulated SOX9, increased the expression of CXCL3/5, recruited neutrophils, and activated the immune system. Additionally, macrophages in the CIP-S group had stronger antigen-presenting abilities and resulted in more CD8 + effective T cells infiltrated.</p><p><strong>Conclusions: </strong>Utilizing single-cell sequencing of BALF, we discovered an enriched population of aberrant basaloid cells in CIP-S patients, which had not been previously reported. Aberrant basaloid cells may upregulate SOX9 via CXCL3/5-CXCR2 to recruit and activate neutrophils, and further activate the immune system, resulting in CIP-S. This finding could identify new targets for stratified treatment of CIP patients, holding promise of a novel approach for clinical guidance.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 4","pages":"128"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536569","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":"Distinct profiles of osteoclast and dendritic cell-mediated expansion and functional activation of NK and T cells.","authors":"Kawaljit Kaur, Anahid Jewett","doi":"10.1007/s00262-025-03956-x","DOIUrl":"10.1007/s00262-025-03956-x","url":null,"abstract":"<p><p>Osteoclasts (OCs) and dendritic cells (DCs) induce expansion and functional activation of NK and T cells. When comparing OCs with DC-induced activation in NK cells, OCs induced significantly higher cell expansion and functional activation of NK cells as compared to DCs, either from healthy individuals or those obtained from cancer patients. However, no differences could be seen in the levels of cell expansion and functional activation in T cells activated by OCs or DCs, either from healthy individuals or those from cancer patients. OCs selectively expanded and activated CD8 + T cells, whereas DCs expanded and activated CD4 + T cells. In addition, both allogeneic and autologous OCs induced similar levels of cell expansion and functional activation of NK and T cells. Together, these findings highlighted the essential roles of OCs in expanding and activating the cytotoxic effectors of NK, and CD8 + T cells, and demonstrated several differences when compared to the effect of DCs.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 4","pages":"127"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536473","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":"Association of lymphocyte subsets percentage with prognosis for recurrent or metastatic nasopharyngeal carcinoma patients receiving PD-L1 inhibitors.","authors":"Jianming Diao, Zhigong Wei, Yiyan Pei, Junyou Ge, Yan Qing, Youneng Wei, Ye Chen, Xingchen Peng","doi":"10.1007/s00262-024-03885-1","DOIUrl":"10.1007/s00262-024-03885-1","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 inhibitors, have demonstrated significant survival benefits in treating recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). While baseline peripheral blood lymphocyte subsets have been identified as prognostic biomarkers in various cancers treated with ICIs, their relevance in R/M-NPC has not been extensively studied.</p><p><strong>Methods: </strong>This post hoc analysis used data from 153 R/M-NPC patients treated with PD-L1 inhibitor monotherapy in the phase 2 trial KL167-2-05-CTP. The lymphocyte subsets, including total T cells, CD4/CD8 ratio, helper T cells, suppressor cytotoxic T cells, NK cells, and B cells, were tested by flow cytometry. These subsets were grouped using optimal cutoff values identified by the Maximally Selected Log-rank Statistic. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox regression analysis, and logistic regression analysis evaluated the associations with objective response rate (ORR) and disease control rate (DCR).</p><p><strong>Results: </strong>Patients with lower NK cell percentages showed significantly longer OS (26.3 vs. 12.1 months, p < 0.001) and PFS (5.5 vs. 3.7 months, p < 0.001) compared to those with higher NK cell percentages. No significant differences in OS or PFS were observed for other lymphocyte subsets. High NK cell percentages were identified as risk factors for shorter OS (HR, 2.49) and PFS (HR, 1.62). There were no significant differences in ORR and DCR between high and low lymphocyte subsets.</p><p><strong>Conclusion: </strong>Lower baseline NK cell percentages are associated with improved OS and PFS in R/M-NPC patients undergoing PD-L1 inhibitor therapy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 4","pages":"129"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536450","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":"Stratification of the immunotypes of tongue squamous cell carcinoma to improve prognosis and the response to immune checkpoint inhibitors.","authors":"Yuya Su, Ryo Ouchi, Pissacha Daroonpan, Miwako Hamagaki, Tohru Ikeda, Noji Rika, Naoto Nishii, Fumihiko Tsushima, Yoshihito Kano, Takahiro Asakage, Makoto Noguchi, Hiroyuki Harada, Miyuki Azuma","doi":"10.1007/s00262-025-03982-9","DOIUrl":"10.1007/s00262-025-03982-9","url":null,"abstract":"<p><strong>Objectives: </strong>An understanding of the tumor immune microenvironment is required to improve treatment, especially the selection of immune checkpoint inhibitors (ICIs). In this study, we stratified the immunotypes of tongue squamous cell carcinoma (TSCC) based on the results of comprehensive immune profiling.</p><p><strong>Methods: </strong>We enrolled 87 therapy-naïve TSCC and 17 ICI-treated TSCC patients who underwent glossectomy without any other prior therapy. Comprehensive immune profile analyses employed multiplex immunofluorescence and tissue imaging.</p><p><strong>Results: </strong>Based on the hierarchies of 58 immune parameters and the spatial distances between cytotoxic T lymphocytes (CTL) and tumor cells, we stratified five immunotypes: Immunoactive type I, border type II, immunosuppressed type III, immunoisolating type IV, and immunodesert type V. The type I frequency was only 16%. Most TSCCs (~ 70%) were of types III-V. The CTL density (CTL-D) was closely correlated with the PD-L1⁺ pan-macrophages (panM)-D, and the panM-D closely correlated with the PD-1⁺ CTL-D. This indicated that PD-1 and PD-L1 expression required macrophages and CTL recruitment in the tumor microenvironment. No ICI-treated TSCC patients, all of whom were recurrent/metastatic cases, were of the type I immunotype, and almost half (47.0%) were of the immunodesert type V. Most cases exhibited an imbalance between T-cell PD-1 and macrophage PD-L1 expression.</p><p><strong>Conclusion: </strong>We defined five TSCC-specific immunotypes based on the results of comprehensive immune profiling analyses. Immunoactive type, which would be sensitive to ICI monotherapy, was rare, and most TSCC cases exhibited immune-regulated immunotypes. Immunotype-based personalized treatments are required to improve clinical outcomes.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 4","pages":"130"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536572","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 tumor-binding antibody with cross-reactivity to viral antigens.","authors":"Michael J Campa, Elizabeth B Gottlin, Kevin Wiehe, Edward F Patz","doi":"10.1007/s00262-025-03975-8","DOIUrl":"10.1007/s00262-025-03975-8","url":null,"abstract":"<p><strong>Background: </strong>We previously identified in non-small cell lung cancer (NSCLC) patients an autoantibody to complement factor H (CFH) that is associated with non-metastatic disease and longer time to progression in patients with stage I disease. A recombinant human antibody, GT103, was cloned from single B cells isolated from patients with the autoantibody. GT103 inhibits tumor growth and establishes an antitumor microenvironment. The anti-CFH autoantibody and GT103 recognize the epitope PIDNGDIT within the SCR19 domain of CFH. Here, we asked if this autoantibody could have originally arisen as a humoral response to a similar epitope in a viral protein from a prior infection.</p><p><strong>Methods: </strong>Homologous viral peptides with high sequence identity to the core PIDNGDIT epitope sequence were identified and synthesized. NSCLC patient plasma containing anti-CFH autoantibodies were assayed by ELISA against these peptides. GT103 was assayed on a 4345-peptide pathogen microarray.</p><p><strong>Results: </strong>Epitopes similar to the GT103 epitope are present in several viruses, including human metapneumovirus-1 (HMPV-1) that contains a sequence within attachment glycoprotein G that differs by one amino acid. Anti-CFH autoantibodies in NSCLC patient plasma weakly bound to an HMPV-1 peptide containing the epitope. GT103 cross-reacted with multiple viral epitopes on a peptide microarray, with the top hits being peptides in the human endogenous retrovirus-K polymerase (HERV-K pol) protein and measles hemagglutinin glycoprotein. GT103 bound the viral HMPV-1, HERV-K pol, and measles epitope peptides but with lower affinity compared to the GT103 epitope peptide.</p><p><strong>Conclusion: </strong>These findings suggest that memory B cells against a viral target could have affinity matured to produce an antibody that recognizes a similar epitope on tumor cells and exhibits antitumor properties.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 4","pages":"126"},"PeriodicalIF":4.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499255","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":"Machine learning-derived prognostic signature integrating programmed cell death and mitochondrial function in renal clear cell carcinoma: identification of PIF1 as a novel target.","authors":"Guangyang Cheng, Zhaokai Zhou, Shiqi Li, Fu Peng, Shuai Yang, Chuanchuan Ren","doi":"10.1007/s00262-025-03967-8","DOIUrl":"10.1007/s00262-025-03967-8","url":null,"abstract":"<p><strong>Background: </strong>The pathogenesis and progression of renal cell carcinoma (RCC) involve complex programmed cell death (PCD) processes. As the powerhouse of the cell, mitochondria can influence cell death mechanisms. However, the prognostic significance of the interplay between mitochondrial function (MF) and PCD remains unclear.</p><p><strong>Methods: </strong>We collected sets of genes related to PCD and MF. Using a powerful machine learning algorithm framework, we investigated the relationship between MF and PCD in different cohorts of patients and developed a machine learning-derived prognostic signature (mpMLDPS) related to MF and PCD. Finally, the most appropriate prognostic markers for RCC were screened by survival analysis and clinical correlation analysis, and the effects on renal cancer cells were analysed in vitro.</p><p><strong>Results: </strong>mpMLDPS was significantly correlated with the prognosis of RCC patients, and the prognosis was worse in the high mpMLDPS group, and this result was also validated in external independent cohorts. There were associations between mpMLDPS and immune checkpoints, tumour microenvironment, somatic mutations, and drug sensitivity. Finally, a novel RCC prognostic marker PIF1 was identified in model genes. The knockdown of PIF1 in vitro inhibited the progression of renal carcinoma cells.</p><p><strong>Conclusion: </strong>mpMLDPS has great potential to serve as a reliable clinical signature to improve the accuracy and reliability of prognostic assessment in RCC patients, thereby choosing the appropriate therapeutic regimen in clinical practice. PIF1 is also expected to be a novel target for the clinical treatment of RCC.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 4","pages":"113"},"PeriodicalIF":4.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11861773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490866","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":"Revealing the role of regulatory b cells in cancer: development, function and treatment significance.","authors":"Ruyu Ye, Sijia Li, Yuxiao Li, Kaixin Shi, Li Li","doi":"10.1007/s00262-025-03973-w","DOIUrl":"10.1007/s00262-025-03973-w","url":null,"abstract":"<p><p>B cells are essential components of the immune response, primarily recognized for their ability to produce antibodies. However, emerging research reveals their important roles in regulating immune responses and influencing tumor development, independent of antibodies. The connection between tumor progression and alterations in the tumor microenvironment is well-established, as immune infiltrating cells can enhance the survival of tumor cells by modifying their surroundings. Despite this, the majority of studies have focused on T cells and macrophages, creating a gap in our understanding of B cells. Regulatory B cells (Bregs) represent a crucial subpopulation that plays a significant role in maintaining immune balance. They may have a substantial impact on tumor immunity by negatively regulating tumor-infiltrating immune cells. This paper reviews the existing literature on Bregs, examining their development, phenotypes, functions, and the mechanisms through which they exert their regulatory effects. Furthermore, we highlight their potential interventional roles and prognostic significance in cancer therapy. By addressing the current gaps in knowledge regarding Bregs within tumors, we hope to inspire further research that could lead to innovative cancer treatments and improved outcomes for patients.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 4","pages":"125"},"PeriodicalIF":4.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11861783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490871","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":"Spatial transcriptomics reveals prognostically LYZ⁺ fibroblasts and colocalization with FN1⁺ macrophages in diffuse large B-cell lymphoma.","authors":"Liyuan Dai, Ning Lou, Liling Huang, Lin Li, Le Tang, Yuankai Shi, Xiaohong Han","doi":"10.1007/s00262-025-03968-7","DOIUrl":"10.1007/s00262-025-03968-7","url":null,"abstract":"<p><strong>Background: </strong>Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous malignancy with diverse patient outcomes, largely influenced by the tumor microenvironment (TME). Understanding the roles of fibroblasts and macrophages within the TME is essential for developing personalized therapeutic strategies in DLBCL.</p><p><strong>Methods: </strong>This study is a multi-omics approach, integrating spatial transcriptomics (n = 11), bulk transcriptomics (n = 2,499), immunohistochemistry (IHC, n = 37), multiplex immunofluorescence (mIF, n = 56), and plasma samples (n = 240) to identify and characterize fibroblast and tumor-associated macrophage subtypes in the TME. Hub genes for LYZ⁺ fibroblasts and FN1⁺ macrophages were selected through univariate Cox regression and random forest analyses. Their prognostic significance was validated using IHC, mIF, and autoantibody assays in DLBCL patients treated with R-CHOP and in non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs).</p><p><strong>Results: </strong>Fibroblasts and macrophages were classified into two distinct subtypes. Patients with higher LYZ⁺ fibroblasts infiltration demonstrated superior prognosis, which was associated with increased infiltration of FN1⁺ macrophages. Key hub genes identified for LYZ⁺ fibroblasts included LYZ, ANPEP, CSF3R, C15orf48, LILRB4, CLEC7A, and COL7A1, while hub FN1⁺ macrophages genes included COL1A1, FN1, APOE, DCN, MMP2, SPP1, COL3A1, and COL1A2. Independent prognostic markers in DLBCL treated with R-CHOP and NSCLC treated with ICIs were identified, including LYZ and LILRB4 at both protein and mRNA levels, and COL1A2 autoantibodies (p < 0.05). In DLBCL patients treated with R-CHOP, FN1 mRNA and autoantibody levels were also prognostic markers (p < 0.05). In NSCLC treated with ICIs, COL3A1 autoantibody was prognostic marker (p < 0.05).</p><p><strong>Conclusions: </strong>This study identified a prognostically relevant LYZ⁺ fibroblasts and FN1⁺ macrophages in DLBCL. The hub genes associated with these subtypes represent potential biomarkers, providing insights into improving patient outcomes in DLBCL.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 4","pages":"123"},"PeriodicalIF":4.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11861843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490885","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":"Harnessing TAGAP to improve immunotherapy for lung squamous carcinoma treatment by targeting c-Rel in CD4+ T cells.","authors":"Peian Cai, Haibo Sun, Tongmeng Jiang, Huawei Li, Dejing Huang, Xiaopei Hao, Wei Wang, Wenqun Xing, Guanghui Liang","doi":"10.1007/s00262-025-03960-1","DOIUrl":"10.1007/s00262-025-03960-1","url":null,"abstract":"<p><p>Revealing the immunosenescence, particularly in CD4+ T cell function in lung squamous carcinoma (LUSC) assists in devising individual treatment strategies. This study identifies differentially expressed genes (DEGs) between ROS1 mutated (ROS1^MUT) and wild-type (ROS1^WT) LUSC samples from the TCGA database. Using WGCNA, immune-related DEGs (IRGs) were screened. Prognostic signatures derived from IRGs were used to compare immune infiltration, chemotherapy sensitivity, and immune-phenotyping score (IPS) between high- and low-risk subgroups. Hub gene abundance in different cell clusters was analyzed via Sc-seq. TAGAP overexpression or silencing was employed to assess its impact on cytokines production and differentiation of CD4+ T cells, downstream c-Rel expression, and tumor progression. High-risk subgroups exhibited decreased infiltration of natural killer, follicular helper T, and CD8+ T cells, but increased plasma, CD4+ memory resting T, and macrophage M2 cells. These subgroups were more sensitive to Sunitinib and CTLA4 blockade. TAGAP expression was significantly reduced in LUSC. Overexpressing TAGAP enhanced CD4+ T cells to produce cytokines, promoted differentiation into Th1/Th17 cells, inhibited Treg conversion, and suppressed LUSC cell phenotype in vitro. TAGAP overexpression in CD4+ T cells also inhibited LUSC tumor growth and boosted immune infiltration in vivo. TAGAP's effects on CD4+ T cells were partly reversed by c-Rel overexpression, highlighting TAGAP's role in rejuvenating CD4+ T cells and exerting anticancer effects by inhibiting c-Rel. This study elucidates the novel therapeutic potential of targeting TAGAP to modulate CD4+ T cell activity in immunotherapy for LUSC.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 4","pages":"114"},"PeriodicalIF":4.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11861500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490865","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}