Pan-cancer analysis of ARID1A Alterations as Biomarkers for Immunotherapy Outcomes

ARID1A alterations would compromise mismatch repair pathway and increase the number of tumor-infiltrating lymphocytes and PD-L1 expression in some cancers, which would cooperate with immune checkpoint inhibitors (ICIs) treatment. However, a comprehensive analysis of ARID1A alteration frequency and its predictive value for ICI treatment outcome in cancers has not yet been investigated. Hence, we performed this pan-cancer analysis to evaluate the prevalence and predictive value of ARID1A alterations across >40,000 cases in multiple cancer types. We found a high frequency (6.2%) of ARID1A, which were associated with significantly higher tumor mutation burden level across various cancers. Importantly, patients with ARID1A alterations and advanced cancers had the substantially prolonged overall survival in ICI treatment cohort, suggesting it might be used to predict a survival benefit from ICI therapy across multiple cancer types. Notably, ARID1A alterations were correlated with markedly high immune infiltrates in endometrial, stomach and colon cancer. However, patients with ARID1A-mutant renal clear cell carcinoma had dramatically lower CD8⁺ T cell infiltrations than those without, indicating the association between ARID1A alterations and immune infiltrates was cancer-dependent. Collectively, our findings highlight the important value of ARID1A alterations as pan-cancer predictive biomarkers for ICI treatment.