ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade

Abstract

ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer1,2. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression3, 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 ARIDIA-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 ARIDIA-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.

Functional loss of ARID1A is tightly associated with high PD‐L1 expression in gastric cancer

“…Conversely, ARID1A inactivation (mostly from inactivating mutations) compromised MMR and increased mutagenesis. In line with our results, the recent study found that tumors formed by an ARID1A‐deficient ovarian cancer cell line in syngeneic mice displayed increased mutational load and PD‐L1 expression . Notably, treatment with anti‐PD‐L1 antibody reduced tumor burden and prolonged the survival of mice bearing ARID1A‐deficient, but not ARID1A‐wild‐type, ovarian tumors .…”

“…One recent study has found that ARID1A can interact with mismatch repair (MMR) protein MSH2 and recruit MSH2 to chromatin during DNA replication and promoting MMR . Conversely, ARID1A inactivation (mostly from inactivating mutations) compromised MMR and increased mutagenesis.…”

A Clinical and Molecular Phase II Trial of Oral ENMD-2076 in Ovarian Clear Cell Carcinoma (OCCC): A Study of the Princess Margaret Phase II Consortium

“…ARID1A may play a role in response to therapy and further investigation is required to establish the impact of ARID1A status for treatment. Recently, a study suggested that ARID1A deficiency contributes to impaired mismatch repair and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy [30].…”

Molecular determinants of complex formation between DNA and the AT‐rich interaction domain of BAF250a

“…The SWI/SNF complexes can be further classified into sub complexes. In most of these cancers, loss of functions due to inactivating mutations in BAF250a is observed [8,9]. BAF250a (ARID1a) gene is evolutionarily conserved and shows sequence similarities with yeast SWI1 and Drosophila protein Osa, which are components of SWI/SNF complexes in these organisms.…”

“…Association of ARID-containing proteins BAF250a (also known as ARID1a) and BAF250b (also known as ARID1b) with the SWI/SNF complex results in BAF-A and BAF-B complexes respectively, whereas the association of ARID-containing BAF200 (also known as ARID2) results in PBAF complex [1][2][3][4]. Of the three ARID-containing proteins in the mammalian SWI/SNF complexes, only BAF250a has been classified as an essential and a tumor suppressor protein [8][9][10]. BAF250a has been shown to have a role in transcriptional co-activation induced by steroid hormones [1].…”