Blocking of CA-MSC-induced desmoplasia reprograms the tumor immune microenvironment and enhances cancer immunotherapy

Abstract

Abstract Cancer associated MSCs (CA-MSCs) are multipotent stromal cells that generate tumor desmoplasia and promote tumor growth. Here, we investigated the impact of CA-MSCs on the ovarian tumor immune microenvironment. In vitro and in vivo analyses confirmed that CA-MSCs secrete numerous cytokines and chemokines, including Ccl2, Cx3cl1 and Tgfb1, that are known to induce the recruitment of monocytes into the tumor and promote macrophage immunosuppressive phenotype. Using a syngeneic and immune responsive murine ovarian tumor model, we found that CA-MSCs restrict the intra-tumoral trafficking of CD8+ T cells and inhibit the response to immune checkpoint inhibitor therapy. Similarly, in patient samples the presence of CA-MSC is inversely correlated with CD8+ T cell infiltration into tumor islets. Single cell RNAseq analyses revealed that tumoral monocytes and macrophages of a-PD-L1 treated-CA-MSCs enriched tumors express high levels of the protein transforming growth factor beta induced (Tgfbi). In ovarian cancer patient samples TGFBI is primarily expressed in the desmoplastic stroma and correlated with poor prognosis. Importantly, we found that hedgehog signaling inhibitor (HHi) therapy reversed CA-MSC driven tumor desmoplasia, reduced the number of tumor-associated myeloid cells and decreased their expression of Tgfbi. These events restored the infiltration and activation of CD8+ T cells into the tumor islets and response to a-PDL1 therapy. We are currently evaluating the role of Tgfbi in the regulation of innate and adaptive immune response. Our findings demonstrated CA-MSCs critically regulate anti-tumor immunity and support HHi as an adjunct to anti-PDL1 therapy to increase repose to immune therapy in ovarian cancer.