Abstract LB-251: Manipulation of macrophage phenotype enhances the apoptotic response to chemotherapy in mesothelioma

Abstract

Abstract Macrophages within the tumor microenvironment (TME) may contribute to tumor chemoresistance. We have found that macrophages constitute a significant percentage of the infiltrating leukocytes in mesothelioma, a highly chemoresistant tumor. We asked whether reprogramming of macrophage phenotype from a Th2 (pro-tumor) to a Th1 (anti-tumor) phenotype would alter the mesothelioma chemoresponsiveness. To address this, we used 3D organotypic models of mesothelioma growth: 1) multicellular spheroids, with mesothelioma cells grown alone or co-cultured with macrophages derived from peripheral blood monocytes, and 2) primary tumor fragment spheroids derived from small fragments of freshly isolated human mesothelioma. Macrophages were incubated with Th1 (LPS & IFNγ) or Th2 (IL-4 &IL-13) cytokines prior to co-culture with mesothelioma spheroids, followed by exposure to standard-of-care chemotherapy, cisplatin plus pemetrexed. Gene expression was evaluated in macrophages to affirm Th1-type (TNF, IL-12, IFNα) versus Th2-type (CD206, IL10) programming. In both spheroid approaches, Th1-type macrophage programming significantly increased the apoptotic response of mesothelioma cells to chemotherapy. Moreover, when CSF1R signaling in macrophages was inhibited by incubation with a small molecular weight kinase antagonist, GW2850, chemoresponsiveness was significantly increased as evidenced by increased presence of apoptotic tumor cells in spheroids. Enhanced chemoresponsiveness of mesothelioma tumor cells was dependent on presence of macrophages because incubation of tumor cells with Th1-type cytokines or GW2850 in the absence of macrophages was without effect. We conclude that manipulating the TME may be a promising therapeutic approach in mesothelioma. This work was supported by a DOD Mesothelioma Program grant PR80717 to Broaddus and Coussens and a T32 Training Grant to Battula and Blakely. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-251. doi:1538-7445.AM2012-LB-251