CXCR1 Expression to Improve Anti-Cancer Efficacy of Intravenously Injected CAR-NK Cells in Mice with Peritoneal Xenografts

Abstract

One reason underlying the failure of current chimeric antigen receptor (CAR) immune therapy to treat solid tumors adequately is insufficient tumor infiltration of CAR immune cells. To address the issue, we electroporated natural killer (NK) cells with two mRNA constructs encoding the chemokine receptor CXCR1 and a CAR targeting tumor-associated NKG2D ligands. The CXCR1-modified NK cells displayed increased migration toward tumor supernatants in vitro and augmented infiltration into human tumors in vivo in subcutaneous and intraperitoneal xenograft models. Most importantly, the cytotoxicity of the CAR-NK cells was not affected by CXCR1 transgene expression, and the enhanced tumor trafficking following intravenous injection resulted in significantly increased antitumor responses in mice carrying established peritoneal ovarian cancer xenografts. Collectively, our findings suggest that the coexpression of CXCR1 and a CAR may provide a novel strategy to enhance therapeutic efficacy of NK cells against solid cancers. Keywords: trafficking, tumor homing, CXCR1, NKG2D, CAR, mRNA, NK, coexpression