TRIM6 ablation reverses ICB resistance in MSS gastric cancer by unleashing cGAS-STING-dependent antitumor immunity.

IF 12.8 1区 医学 Q1 ONCOLOGY
Yinan Niu, Chen Ding, Quansheng Wang, Jingyi Yin, Lingmeng Li, Wenshuai Liu, Xuefei Wang, Liyu Huang
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引用次数: 0

Abstract

Background: Gastric cancers are classified into four molecular subtypes according to The Cancer Genome Atlas (TCGA) classification: Epstein-Barr virus-positive (EBV-positive), microsatellite instability-high (MSI-H), chromosomal instability (CIN), and genomically stable (GS). Unlike MSI-H gastric cancer, GS and CIN subtypes exhibit immunologically inert microenvironments and demonstrate minimal response to immune checkpoint blockade (ICB), necessitating novel strategies to overcome immunotherapy resistance.

Methods: Through weighted gene co-expression network analysis (WGCNA), we identified the E3 ubiquitin ligase TRIM6 as inversely associated with MSI-H status. TRIM6-knockout murine models and subcutaneous tumors were subjected to flow cytometry, RNA sequencing, immunoblotting, and ubiquitination assays to characterize tumor-infiltrating lymphocytes (TILs), pathway activation, and TRIM6-mediated regulation of the cGAS-STING axis.

Results: Hypermethylation-mediated TRIM6 downregulation distinguished MSI-H from microsatellite stable (MSS) gastric cancers. Clinically, TRIM6 expression inversely correlated with cytotoxic T lymphocyte (CTL) infiltration and anti-PD-1/PD-L1 therapeutic efficacy. Mechanistically, TRIM6 catalyzed K27-linked polyubiquitination of cGAS, triggering its proteasomal degradation and consequent suppression of the cGAS-STING pathway. TRIM6 ablation enhanced CD8+ T lymphocytes infiltration via cGAS-mediated innate immune response and synergized with anti-PD-L1 therapy in MSS gastric tumors.

Conclusions: Our results elucidate TRIM6-mediated suppression of antitumor immunity as a novel mechanism underlying ICB resistance in MSS gastric cancer, positioning TRIM6 as both a predictive biomarker and therapeutic target for immunologically cold subtypes.

TRIM6消融通过释放cgas - sting依赖的抗肿瘤免疫逆转MSS胃癌的ICB耐药。
背景:根据癌症基因组图谱(TCGA)分类,胃癌可分为eb病毒阳性(ebv阳性)、微卫星不稳定-高(MSI-H)、染色体不稳定(CIN)和基因组稳定(GS)四种分子亚型。与MSI-H型胃癌不同,GS和CIN亚型表现出免疫惰性微环境,对免疫检查点阻断(ICB)的反应最小,需要新的策略来克服免疫治疗耐药性。方法:通过加权基因共表达网络分析(WGCNA),我们发现E3泛素连接酶TRIM6与MSI-H状态呈负相关。对trim6敲除小鼠模型和皮下肿瘤进行流式细胞术、RNA测序、免疫印迹和泛素化检测,以表征肿瘤浸润淋巴细胞(TILs)、通路激活和trim6介导的cGAS-STING轴调控。结果:高甲基化介导的TRIM6下调将MSI-H与微卫星稳定型(MSS)胃癌区分开来。临床上,TRIM6表达与细胞毒性T淋巴细胞(CTL)浸润及抗pd -1/PD-L1治疗效果呈负相关。在机制上,TRIM6催化了k27连接的cGAS多泛素化,触发其蛋白酶体降解,从而抑制cGAS- sting途径。TRIM6消融术通过cgas介导的先天免疫反应增强MSS胃肿瘤中CD8+ T淋巴细胞浸润,并与抗pd - l1治疗协同作用。结论:我们的研究结果阐明了TRIM6介导的抗肿瘤免疫抑制是MSS胃癌中ICB耐药的新机制,将TRIM6定位为免疫冷亚型的预测性生物标志物和治疗靶点。
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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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