Somatic ARID1A mutation stratifies patients with gastric cancer to PD-1 blockade and adjuvant chemotherapy,Cancer Immunology, Immunotherapy

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Somatic ARID1A mutation stratifies patients with gastric cancer to PD-1 blockade and adjuvant chemotherapy
Cancer Immunology, Immunotherapy ( IF 4.6 ) Pub Date : 2022-11-12 , DOI: 10.1007/s00262-022-03326-x
Yun Gu _{1,

2} , Puran Zhang ₁ , Jieti Wang ₃ , Chao Lin ₂ , Hao Liu ₂ , He Li ₂ , Hongyong He ₂ , Ruochen Li ₂ , Heng Zhang ₂ , Weijuan Zhang ₄

Affiliation

Background

AT-rich interaction domain 1A (ARID1A) encodes a vital component of switch/sucrose non-fermentable chromatin-remodeling complex. Given its association with genomic instability, we conducted this study to determine whether ARID1A mutation status had an impact on therapeutic responsiveness in gastric cancer (GC), especially combinatory chemo-immunotherapy.

Methods

We retrospectively enrolled a total of 1162 patients from five independent cohorts. ZSHS Cohort and TCGA Cohort were designed to inform chemotherapeutic relevance and immunobiology of ARID1A-mutant GC based on tissue samples and sequencing data, respectively. MSKCC Cohort, mGC Cohort, and Melanoma Cohort were utilized to interrogate the predictive efficacy of ARID1A mutation to programmed cell death protein 1 (PD-1) blockade.

Results

ARID1A mutation was enriched in EBV-positive, hypermutated-single nucleotide variant and microsatellite-unstable subtype GC, and was predictive of responsiveness to both fluorouracil-based chemotherapy and PD-1 blockade. Specifically, ARID1A mutation score was a highly sensitive indicator (91%) of response to pembrolizumab. Mechanistically, ARID1A mutation correlated with extensive DNA damage repair deficiency and immunogenic tumor microenvironment (TME) featured by elevated activated subsets of CD8⁺ T cells, CD4⁺ T cells, and NK cells. Type 17T helper cells were typically abundant in ARID1A-mutant GC and might be a precondition for chemosensitivity conferred by ARID1A mutation. Furthermore, ARID1A mutation indicated elevated expression of VEGFA and CLDN18, as well as over-representation of ERBB2 and FGFR2 signaling pathway.

Conclusions

ARID1A-mutant GC displayed immunogenic TME and might be a candidate for both monotherapy and the combination of frontline chemotherapy and PD-1 blockade.

中文翻译：

体细胞 ARID1A 突变使胃癌患者接受 PD-1 阻断和辅助化疗

背景

富含 AT 的相互作用域 1A (ARID1A) 编码开关/蔗糖不可发酵染色质重塑复合物的重要组成部分。鉴于其与基因组不稳定性的关联，我们进行了这项研究以确定ARID1A突变状态是否对胃癌 (GC) 的治疗反应有影响，尤其是联合化学免疫疗法。

方法

我们回顾性地招募了来自五个独立队列的总共 1162 名患者。ZSHS 队列和 TCGA 队列旨在分别根据组织样本和测序数据告知ARID1A突变 GC 的化疗相关性和免疫生物学。MSKCC 队列、mGC 队列和黑色素瘤队列被用于研究ARID1A突变对程序性细胞死亡蛋白 1 (PD-1) 阻断的预测功效。

结果

ARID1A突变在 EBV 阳性、超突变单核苷酸变异和微卫星不稳定亚型 GC 中富集，并预测对基于氟尿嘧啶的化疗和 PD-1 阻断的反应性。具体而言，ARID1A突变评分是对派姆单抗反应的高度敏感指标 (91%)。从机制上讲，ARID1A突变与广泛的 DNA 损伤修复缺陷和免疫原性肿瘤微环境 (TME) 相关，其特征是 CD8 ⁺ T 细胞、CD4 ⁺ T 细胞和 NK 细胞的活化亚群升高。17T 型辅助细胞通常在ARID1A突变体 GC 中很丰富，可能是ARID1A赋予化学敏感性的先决条件突变。此外，ARID1A突变表明VEGFA和CLDN18的表达升高，以及ERBB2和FGFR2信号通路的过度表达。