Microenvironment and Immunology STAT3 Inhibition Enhances the Therapeutic Efficacy of Immunogenic Chemotherapy by Stimulating Type 1 Interferon Production by Cancer

STAT3 is an oncogenic transcription factor with potent immu-nosuppressive functions. We found that pharmacologic inhibi-tionof STAT3or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based che-motherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immu-nocompetent (not in immunodeficient) mice. As compared with Stat3-sufficient control tumors, Stat3/ cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lympho-cytes 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–depen-dent and T lymphocyte–mediated anticancer immune response. Among these therapy-relevant stress pathways, Stat3/ cancer cellsmanifested one significant improvement, namely an increase in the expression of multiple type-1 interferon-responsive genes, including that of the chemokinesCxcl9 andCxcl10. This enhanced type-1 interferon response could be suppressed by reintroducing wild-type Stat3 (but not a transactivation-deficient mutant Stat3Y705F) into the tumor cells. This maneuver also abolished the improved chemotherapeutic response of Stat3/ 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 chemother-apeutic response between Stat3/ and control tumors. Altogeth-er, these results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells. Cancer Res; 75(18); 1–11. 2015 AACR