UC San Diego

Tumor associated macrophages (TAMs) are a major component in the tumor microenvironment. TAMs are associated with poor prognosis in solid tumors and promote an immunosuppressive environment, which can result from persistent inflammation. Preclinical studies suggest boosting existing immunotherapies by reprogramming TAMs from a pro-tumor phenotype towards an anti-tumor one. To better target these TAMs, we must look at the complexes that regulate them. The BAF complex, an ATP-dependent chromatin remodeler, regulates gene expression by altering the position of nucleosomes to promote gene expression. ARID1A, a core protein subunit of cBAF plays a vital role in the epigenetic regulation of inflammatory genes and the differentiation of myeloid cells. Little is known about the effects of Arid1a loss in TAMs and its implications in cancer. We sought to recapitulate the effects of Arid1a loss on macrophages in vitro, investigate the mechanisms driving the associated phenotype, and assess phagocytotic function in Arid1a-deficient (Arid1aKO) TAMs. Using an in vitro system of bone marrow derived macrophages (BMDMs), we observed that Arid1aKO macrophages upregulated the inhibitory ligand PD-L1 (programmed death ligand-1) and CD86. This upregulation is both JAK1/2 and type I interferon signaling independent and operates through a cell intrinsic mechanism. Furthermore, we found that Arid1aKO TAMs displayed similar phagocytic capabilities to Arid1a-intact TAMs. Our results demonstrate that upregulation of PD-L1 and CD86 in macrophages that occurs upon Arid1a loss may explain enhanced response to anti-PD-L1 immunotherapy. In the future, these results can help further direct preclinical models/strategies aimed at reprogramming macrophages as a cancer therapeutic.