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Pancreatic cancer cells are known to shield themselves from immunosurveillance by secreting immune inhibitory cytokines such as Interleukin-10. Using mesothelin, a differentiating antigen that is overexpressed in pancreatic cancer, we assessed the negative effect of the tumor microenvironment on chimeric antigen receptor T cell–based immunotherapy and its reversal via depletion of Interleukin-10.T cells cultured in pancreatic cancer–cell-conditioned medium were transduced with lentiviruses encoding mesothelin–chimeric antigen receptor in the presence or absence of anti-Interleukin-10–blocking antibody.Coculture supernatants of conditioned medium displayed significant inhibition of interferon γ and granzyme B secretion, both of which are crucial for induction of target cell cytotoxicity. In contrast, this inhibition was restored toward baseline when conditioned medium was Interleukin-10– depleted (p < .05 for both interferon γ and granzyme B). In addition, we observed a significant decrease in mesothelin–chimeric antigen receptor T cell–induced cytotoxicity of BxPC-3 target cells in the presence of conditioned medium. Furthermore, we observed a partial blunting of this inhibition when Interleukin-10 was depleted from the conditioned medium.Substantial reversal of tumor-derived immunosuppression may be achieved by blocking Interleukin-10 in the local microenvironment, allowing for more effective cytotoxicity of mesothelin-engrafted chimeric antigen receptor T cells and enhancing the potential for clinical application.