CCL22 is upregulated in cancer cells in response to paracrine signaling by STING-activated myeloid cells

Solid tumors can evolve mechanisms that facilitate evasion of anti-tumor immune responses. Recruitment of regulatory T cells (Tregs) to the tumor microenvironment, which can inhibit cell-mediated immunity, represents one such strategy. A well-described mechanism of Treg recruitment occurs via the chemokine CCL22. Our lab and others have shown that CCL22 is upregulated in cancer cells via activation of the ST imulator of IN terferon G enes (STING). STING triggers robust immune responses against cytoplasmic DNA, which can accumulate in cancer cells due to chromosomal instability, damaged mitochondria, and increased expression of LINE-1 retrotransposons. LINE-1 is highly upregulated in many cancer types, and LINE-1 activation of STING in cancer cells may have clinically relevant outcomes on anti-tumor immunity. STING has been associated with both anti- and pro-tumor immune responses, and a potential mechanism of STING-mediated immune evasion is through CCL22 upregulation. CCL22 was first characterized in macrophages, and here we investigate the effects of STING activation on CCL22 expression in macrophages and monocytes. We find that human macrophages and monocytes are resistant to CCL22 upregulation by STING, but that STING-activated macrophages and monocytes release unidentified paracrine factor(s) that dramatically increase CCL22 upregulation in cancer cells. This increase exceeds upregulation induced by direct, pharmacological activation of STING. Moreover, we found that the activity of the paracrine factors on CCL22 requires intact STING in cancer cells, as evidenced by the inability of STING knockout cells to upregulate CCL22 in response to these factors.