Loss of ARID1A expression is associated with worse survival and reduced tumor infiltrating lymphocytes in advanced clear cell renal cell carcinoma

BACKGROUND: Patients with metastatic clear cell renal cell carcinoma (ccRCC) are often treated with immunotherapy (ICI), with no definitive biomarkers of response. ARID1A is mutated among ICI responders in several cancer types, including ccRCC. Immunohistochemistry (IHC) is a widely available method of detecting ARID1A protein levels. Assessment of tumor infiltrating immune cells (TILs) also has been linked to ICI response in some studies. PATIENTS AND METHODS: We explored the expression of ARID1A protein using IHC (manual and QuPath) in a cohort of 29 patients with metastatic ccRCC who had undergone cytoreductive nephrectomy (CRN). We correlated ARID1A expression with clinicopathological data, survival, and TILs. We corroborated our IHC results in 488 cases from the TCGA-KIRC dataset, and utilized immune deconvolution platforms to define changes in TILs in relation to ARID1A in TCGA-KIRC and an ICI-therapy validation cohort. RESULTS: Low ARID1A protein expression is associated with large tumor size, lymphovascular invasion, high stage, low TILS, and worse overall survival. Low ARID1A mRNA in TCGA-KIRC similarly had significantly worse survival and were immune cold histologically and in ESTIMATE immune score. xCell showed significant enrichment of Th1, Th2, myeloid dendritic cells, macrophages, and T NK cells in low ARID1A mRNA ccRCC with elevation of Tregs in tumors that have high ARID1A. CONCLUSION: patients who receive ICI therapy. ARID1A IHC provides comparable results to bulk mRNA analysis, suggesting that it can be reliably used to explore ARID1A as a potential ICI biomarker in ccRCC.