ARID2 deficiency correlates with the response to immune checkpoint blockade in melanoma

Abstract The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeler family includes the BRG1-associated factor (BAF) and polybromo BRG1-associated factor (PBAF) complexes. AT-rich interactive domain-containing protein 2 (ARID2), encoding a PBAF complex subunit, is frequently mutated in melanoma independently of BRAF/RAS mutations. Emerging evidence shows that SWI/SNF complexes regulate tumor immunity; for instance, the loss of polybromo 1 (PBRM1), another PBAF complex subunit, enhances susceptibility to immune checkpoint inhibitors (ICIs) in melanoma. Notably, ARID2 mutations are more frequent in melanoma compared to PBRM1 mutations. However, the role of ARID2 as a modulator of tumor immunity remains unclear. Here, we show that ARID2 knockout sensitizes melanoma to ICIs. Anti-PD-L1 treatment restricts tumor growth in mice bearing ARID2-knockout melanoma cells, correlating with an increase in the infiltration of cytotoxic CD8+ T cells. Further, ARID2 deficiency leads to STAT1 upregulation, which subsequently causes increased expression of T cell-attracting chemokines such as CXCL9, CXCL10, and CCL5. These results demonstrate that ARID2 is an immunomodulator and a potential biomarker that indicates ICI effectiveness in patients with melanoma.