Targeting the vulnerability of arachidonic acid metabolism to enhance immunotherapy efficacy in ARID1A-deficient colorectal cancer [RNA-Seq]

ARID1A, a core constituent of SWI/SNF complex, is mutated in about 10% of colorectal cancer (CRC). This study demonstrates a synergistic effect of arachidonic acid metabolism inhibitors with immune checkpoint inhibitors (ICIs) by regulating functionality of CD8+ T cells and vasculogenic mimicry (VM) formation in ARID1A-deficient CRC. Mechanistically, ATAC-seq and ChIP-qPCR demonstrated that the lack of ARID1A results in reduced levels of the key enzymes PTGS1 and PTGS2, which control the arachidonic acid pathway. This reduction generated a reliance on the remaining functionality of arachidonic acid pathway in ARID1A-deficient cells. Overall design: This study conducted RNA-seq analysis on ARID1A wild-type and mutant cell lines, and further enriched differentially expressed genes

ARID1A是SWI/SNF复合物（SWI/SNF complex）的核心组成成分，在约10%的结直肠癌（colorectal cancer, CRC）中发生突变。本研究证实，花生四烯酸代谢抑制剂与免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）可发挥协同效应，其机制为通过调控ARID1A缺陷型结直肠癌中CD8阳性T细胞（CD8+ T cells）的功能及血管生成拟态（vasculogenic mimicry, VM）的形成。机制上，ATAC-seq（assay for transposase-accessible chromatin with high-throughput sequencing）与ChIP-qPCR（chromatin immunoprecipitation-quantitative PCR）实验结果显示，ARID1A缺失会导致调控花生四烯酸通路的关键酶PTGS1与PTGS2的表达水平下调，该缺失使得ARID1A缺陷细胞依赖于花生四烯酸通路的剩余功能。总体实验设计：本研究对ARID1A野生型与突变型细胞系开展了RNA-seq（RNA sequencing）分析，并进一步对差异表达基因进行富集分析。