ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer^1,2. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression ³ , which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy.

中文翻译：

---

ARID1A缺乏症会促进变异性，并增强免疫检查点封锁释放的治疗性抗肿瘤免疫力。

ARID1A（富含AT的相互作用域1A，也称为BAF250a）是癌症^1,2中最常见的突变基因之一。大多数ARID1A突变是失活突变，并导致ARID1A表达缺失³，这使ARID1A成为不良的治疗靶标。因此，鉴定在ARID1A突变型肿瘤中产生治疗脆弱性的ARID1A缺乏症的分子后果具有临床意义。在蛋白质组学筛选中，我们发现ARID1A与错配修复（MMR）蛋白MSH2相互作用。ARID1A在DNA复制过程中将MSH2募集到染色质上，并促进了MMR。相反，ARID1A失活损害了MMR并增加了诱变作用。ARID1A缺乏与微卫星不稳定性基因组特征和主要的C> T突变模式以及跨多种人类癌症的突变负荷增加有关。在同系小鼠中，由ARID1A缺陷型卵巢癌细胞系形成的肿瘤显示出增加的突变负荷，升高的肿瘤浸润淋巴细胞数量和PD-L1表达。尤其，抗PD-L1抗体治疗可减轻携带ARID1A缺陷但非ARID1A野生型卵巢肿瘤的小鼠的肿瘤负担并延长其存活时间。总之，这些结果表明，ARID1A缺乏会导致癌症中的MMR和突变表型受损，并可能与免疫检查点封锁疗法配合使用。