Data from STAT3 Inhibition Enhances the Therapeutic Efficacy of Immunogenic Chemotherapy by Stimulating Type 1 Interferon Production by Cancer Cells

<div>Abstract<p>STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacologic inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice. As compared with <i>Stat3</i>-sufficient control tumors, <i>Stat3</i><sup>−/−</sup> cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lymphocytes after chemotherapy. Anthracyclines are known to induce several stress pathways that enhance the immunogenicity of dying and dead cancer cells, thereby stimulating a dendritic cell–dependent and T lymphocyte–mediated anticancer immune response. Among these therapy-relevant stress pathways, <i>Stat3</i><sup>−/−</sup> cancer cells manifested one significant improvement, namely an increase in the expression of multiple type-1 interferon-responsive genes, including that of the chemokines <i>Cxcl9</i> and <i>Cxcl10</i>. This enhanced type-1 interferon response could be suppressed by reintroducing wild-type <i>Stat3</i> (but not a transactivation-deficient mutant <i>Stat3</i><sup>Y705F</sup>) into the tumor cells. This maneuver also abolished the improved chemotherapeutic response of <i>Stat3</i><sup>−/−</sup> cancers. Finally, the neutralization of the common type-1 interferon receptor or that of the chemokine receptor CXCR3 (which binds CXCL9 and CXCL10) abolished the difference in the chemotherapeutic response between <i>Stat3</i><sup>−/−</sup> and control tumors. Altogether, these results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells. <i>Cancer Res; 75(18); 3812–22. ©2015 AACR</i>.</p></div>