肿瘤内源性ENO1抑制可促进抗肿瘤免疫反应,促进抗pd - l1免疫治疗在膀胱癌中的疗效。

IF 12.8 1区 医学 Q1 ONCOLOGY
Chengquan Shen, Jing Liu, Ding Hu, Changxue Liu, Fei Xie, Yonghua Wang
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引用次数: 0

摘要

免疫疗法已经彻底改变了癌症治疗,但了解免疫疗法的耐药机制仍然具有挑战性。在这里,CRISPR cas9在体内筛选和临床免疫治疗耐药BC样本的rna测序发现烯醇化酶1 (ENO1)是抗pd - l1治疗效果的有效调节因子。临床BC样本的研究表明,ENO1过表达与BC中免疫逃避之间存在相关性,这可以通过CD8+ T细胞浸润减少和抗pd - l1治疗的抵抗来证明。CD8+ T细胞浸润和功能的增加表明抗肿瘤免疫,这是由ENO1敲低引起的,同时也抑制了癌变。单细胞RNA测序表明,野生型(WT)和ENO1敲除(KO)肿瘤具有不同的免疫细胞组成,后者更倾向于免疫刺激微环境。在机制上,ENO1在TME中通过SPP1-ITGA4/ITGB1通路调节CD8+ T细胞功能和肿瘤相关巨噬细胞(TAM)极化。重要的是,ENO1的遗传和药理抑制使肿瘤对抗肿瘤免疫变得敏感,并与抗pd - l1治疗协同作用。结果表明,肿瘤固有的ENO1是BC中肿瘤免疫逃避的关键调节因子。以ENO1为靶点,通过促进抗肿瘤免疫,提高免疫检查点阻断治疗的疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tumor-intrinsic ENO1 inhibition promotes antitumor immune response and facilitates the efficacy of anti-PD-L1 immunotherapy in bladder cancer.

Immunotherapy has revolutionized cancer treatment, yet understanding immunotherapy resistance mechanisms remains challenging. Here, a CRISPR cas9 screening in vivo and an RNA-sequencing for clinical immunotherapy resistance BC samples identified enolase 1 (ENO1) as a potent regulator of anti-PD-L1 treatment efficacy. Investigation of clinical BC samples demonstrated a correlation between ENO1 overexpression and immune evasion in BC, evidenced by reduced CD8+ T cell infiltration and resistance to anti-PD-L1 therapy. Increased CD8+ T cell infiltration and function were indicative of antitumor immunity, which was elicited by ENO1 knockdown, which also suppressed carcinogenesis. Single-cell RNA sequencing demonstrated that wild-type (WT) and ENO1 knockout (KO) tumors have different immune cell compositions with the latter preferring an immunostimulatory microenvironment. Mechanistically, ENO1 regulated CD8+ T cell function and tumor-associated macrophage (TAM) polarization via the SPP1-ITGA4/ITGB1 pathway in the TME. Importantly, genetic and pharmacological inhibition of ENO1 sensitizes tumors to anti-tumor immunity and synergizes with anti-PD-L1 therapy. The results highlight tumor-intrinsic ENO1 as a critical regulator of tumor immune evasion in BC. Targeting ENO1 enhance the efficacy of immune checkpoint blockade therapy by promoting antitumor immunity.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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