Interferon regulatory factor 3 upregulates the Treg recruitment factor CCL22 in response to double-stranded DNA in cancer cells

Abstract

Cancer immunotherapy holds great promise for the treatment of solid tumors, but its effectiveness is hindered by the recruitment of regulatory T cells (Tregs), which inhibit anti-tumor immune responses. We report here that cytosolic dsDNA, a characteristic of many cancer cells, upregulates expression of the Treg-recruitment chemokine CCL22 in multiple types of malignant epithelial cells. We also identified that interferon regulatory factor 3 (IRF3) is a key regulator of CCL22 in response to dsDNA. Both IRF3 and NF-{kappa}B are activated downstream of the stimulator of interferon genes (STING), a primary effector protein responding to multiple cytosolic dsDNA sensors. IRF3 activation by STING triggers robust expression of type I interferons, which can boost anti-tumor immune responses. Thus, STING agonists have been used clinically to activate IRF3 during immunotherapy. However, STING activation in some cases is reported to paradoxically foster a pro-tumor, immunosuppressive environment. Our finding that IRF3 regulates CCL22 in response to dsDNA suggests a possible mechanism contributing to STING-mediated immunosuppression. In addition, we found that cultured cancer cells appear able to evolve mechanisms to co-opt nucleic acid sensing pathways to upregulate CCL22, suggesting that these pathways may contribute to acquired immune evasion in tumors with increased cytosolic dsDNA.