Effect of the loss of the type III TGFβ receptor during tumor progression on tumor microenvironment: Preclinical development of TGFβ inhibition and TGFβ-related biomarkers to enhance immunotherapy efficacy.

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10563 Background: Overall, the clinical efficacy of tumor immunotherapy has been limited. Our incomplete understanding of the complex interplay between tumors and the immune microenvironment has contributed to these modest outcomes. Our work has revealed that several tumors downregulate the expression of the type III TGFβ receptor (TβRIII) with progression. TβRIII is shed from the cell surface to generate soluble TβRIII (sTβRIII) which is capable of sequestering TGFβ. Methods and Results: Using both breast cancer and melanoma tumor models we have demonstrated that the loss of TβRIII expression is associated with diminished tumor infiltrating CD8+ T cells and increased regulatory T cells (Tregs) within the tumor microenvironment. Our data implies that these alterations correlate with suppressed tumor antigen-specific T cell responses and more rapid disease progression. We show that these changes are due to enhanced TGFβ signaling within the immune compartment of the tumor microenvironment resulting in enhanced expression of the indoleamine 2,3-dioxygenase immunoregulatory enzyme by local plasmacytoid dendritic cells (DCs) as well as increased expression of the Treg-recruiting CCL22 chemokine by local myeloid DCs. Microarray analysis indicates that these same gene expression associations also exist in human breast cancers. Consistent with these studies, we have demonstrated that TGF-β inhibition synergistically enhances the efficacy of a Her2/neu vaccine in a breast cancer model and that plasma levels of sTβRIII correlate with clinical response and overall survival in stage III melanoma patients. Conclusions: We have elucidated a novel mechanism that tumors utilize to suppress the generation of anti-tumor immunity by establishing a link between the loss of an endogenous suppressor of tumor metastasis, TβRIII, and the generation of an immunotolerant tumor microenvironment. We are pursuing a phase I clinical trial to investigate the efficacy of combining a TGF-β inhibitor with a tumor vaccine while also determining if sTβRIII may function as a predictive biomarker for this approach.