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

Abstract

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