Targeted inhibition in stromal TGFβ activity in pancreatic cancer

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Transforming growth factor β (TGFβ) is an attractive therapeutic target in cancer. However, blocking TGFβ in pancreatic cancer (PDA) has not been successful in clinical studies. This is due part to the fact that TGFβ signaling suppresses pancreatic cancer cell growth in a context- dependent manner. In contrast, TGFβ signaling in stromal cells promotes to tumor progression by inducing fibrosis and immunosuppression, characteristics of PDA. Moreover, we have identified TGFβ-stimulated fibroblasts produce cytokines that limit innate immune cell activity. For example, IL-6 production by PDA associated fibroblasts reduces NK cell activity that facilitates PDA metastasis. Using species specific tools we demonstrated that selective inhibition of stromal TGFβ signaling reduces PDA metastasis in mice bearing PDA xenografts and also promotes an epithelial tumor cell phenotype and an altered immune microenvironment. These observations strongly suggest a TGFβ-driven paracrine network between stromal cells and tumor cells in PDA that promotes tumor progression. Up to 60% of human PDA have tumor cell specific deficiency in canonical TGFβ signaling via loss of TGFβ receptor 2 (TGFβR2) or the downstream signal mediator SMAD4. Here we propose that selective inhibition of TGFβ signaling in stromal cells in PDA that harbors epithelial mutations in TGFβ signaling will dramatically and safely enhance the efficacy of chemotherapy and/or immune therapy. To delineate the mechanisms involved and test this novel strategy, we propose the following aims: 1, Identify TGFβ signaling in cancer associated fibroblasts that drive PDA progression; 2, Determine the effect of stromal TGFβ inhibition on the efficacy of chemotherapy and checkpoint blockade in models of TGFβ mutant PDA. If proven correct this would provide a rationale to stratify PDA patients such that those with tumor cell mutations in TGFβ signaling would be candidates for inhibition of stromal TGFβ signaling in combination with standard therapy or immune therapy.