Multiple regulatory processes within the tumor microenvironment work in concert to limit local anti-tumor immunity, and it is likely that integrative cancer therapies that target multiple cellular components in the tumor will be required to optimize antitumor immunity. Sorafenib is a promiscuous small molecule tyrosine kinase inhibitor developed as an anti-angiogenesis agent. We have previously shown that Sorafenib treatment can shift bone-marrow derived macrophages activated with lipopolysaccharide (LPS) and prostaglandin E2 (PGE2) from the pro-tumorigenic IL-10 secreting phenotype to the anti-tumor IL-12 secreting phenotype. Here, we extend these studies to explore the effect of Sorafenib on tumor-associated macrophages (TAMs) in a murine model of HER2+ breast cancer. Sorafenib treatment effectively delays the outgrowth of HER-2-overexpressing tumors in FVB/N mice relative to vehicle-treated controls. Immunohistochemical analysis revealed increased infiltration of F480+ macrophages in Sorafenib-treated tumors. F480+ TAMs isolated from Sorafenib-treated tumors had greater levels of IL-12 gene expression, and secreted higher levels of monocyte chemotactic protein-1 (MCP-1); there was no difference in IL-10 gene expression. Furthermore, F480+ TAMs isolated from Sorafenib-treated tumors demonstrated a superior ability to stimulate CD4+ T cell proliferation, and intracellular cytokine staining of tumor infiltrating lymphocytes isolated from Sorafenib-treated tumors showed an increase in CD4+ IFNγ-secreting T cells. Taken together, these data suggest that Sorafenib may alter the activation state of TAMs to increase pro-immunogenic signals and promote T helper type 1 immunity in the tumor microenvironment.
Citation Format: Melek M. Sunay, James M. Leatherman, Gang Chen, Leisha A. Emens. Sorafenib modulates macrophages to promote T helper type 1 immunity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3985. doi:10.1158/1538-7445.AM2013-3985