Harnessing TAGAP to improve immunotherapy for lung squamous carcinoma treatment by targeting c-Rel in CD4+ T cells.

IF 4.6 2区 医学 Q2 IMMUNOLOGY
Peian Cai, Haibo Sun, Tongmeng Jiang, Huawei Li, Dejing Huang, Xiaopei Hao, Wei Wang, Wenqun Xing, Guanghui Liang
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Abstract

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 (ROS1MUT) and wild-type (ROS1WT) 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.

利用TAGAP靶向CD4+ T细胞中的c-Rel改善肺鳞癌的免疫治疗。
揭示肺鳞癌(LUSC)的免疫衰老,特别是CD4+ T细胞功能,有助于制定个性化的治疗策略。本研究从TCGA数据库中鉴定了ROS1突变(ROS1MUT)和野生型(ROS1WT) LUSC样本之间的差异表达基因(DEGs)。使用WGCNA筛选免疫相关deg (IRGs)。来自IRGs的预后特征用于比较高、低风险亚组之间的免疫浸润、化疗敏感性和免疫表型评分(IPS)。通过Sc-seq分析Hub基因在不同细胞群中的丰度。采用TAGAP过表达或沉默来评估其对细胞因子产生和CD4+ T细胞分化、下游c-Rel表达和肿瘤进展的影响。高危亚组表现出自然杀伤、滤泡辅助T和CD8+ T细胞浸润减少,但血浆、CD4+记忆静息T和巨噬细胞M2细胞浸润增加。这些亚组对舒尼替尼和CTLA4阻断更为敏感。TAGAP在LUSC中的表达显著降低。在体外,过表达TAGAP可增强CD4+ T细胞产生细胞因子,促进向Th1/Th17细胞分化,抑制Treg转化,抑制LUSC细胞表型。在体内,CD4+ T细胞中TAGAP的过表达也抑制了LUSC肿瘤的生长,促进了免疫浸润。TAGAP对CD4+ T细胞的作用被c-Rel过表达部分逆转,这表明TAGAP可以通过抑制c-Rel来激活CD4+ T细胞并发挥抗癌作用。这项研究阐明了靶向TAGAP调节CD4+ T细胞活性在LUSC免疫治疗中的新治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
10.50
自引率
1.70%
发文量
207
审稿时长
1 months
期刊介绍: Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions. The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.
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