Inhibition of Interleukin-10 in the tumor microenvironment can restore mesothelin chimeric antigen receptor T cell activity in pancreatic cancer in vitro

    loading  Checking for direct PDF access through Ovid


Background.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.Methods.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.Results.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.Conclusion.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.

    loading  Loading Related Articles