Engineering of Chimeric Antigen Receptor T Cells with Integrin αEβ7 Results in Augmented Therapeutic Efficacy Against E-Cadherin Positive Tumor

Abstract

Integrin αEβ7 (CD103) can interact with E-cadherin and promote T cell retention in epithelial tissue. However, whether the expression of CD103 on chimeric antigen receptor (CAR)-T cells may augment T cell antitumor activity remains unknown. Using a preclinical model, we demonstrate that CD103 engineering of human CAR-T cells significantly improves their therapeutic effects on eliminating pre-established E-cadherin expressing tumor cells in immune deficient NOD.scid.Il2Rγcnull (NSG) mice. Human T cells that were engineered with CAR containing 4-1BB and CD3zeta intracellular signaling domains (named BBz) expressed reduced level of CD103 in mice model. Ex vivo assays confirmed the effect of 4-1BB on repressing CD103 expression in CAR-T cells. On the other hand, we generated CD103 expressing CAR-T cells by introducing the αE gene into the CAR structure (named CD103-BBz CAR-T cells). As compared to BBz CAR-T cells, CD103-BBz CAR-T cells produced higher levels of IL-2 and underwent greater expansion in cultures and acquired greater capacity to control the growth and metastasis of E-cadherin expressing lymphoma cells in NSG mice. This effect of CD103-BBz CAR-T cells was associated with their increased capacity to infiltrate into the tumor and persist in vivo, leading to significantly improved overall survival of lymphoma mice. Our findings suggest that engineering tumor-reactive T cells with CD103 may represent a novel strategy to improve adoptive T cells anti-tumor efficacy, and this strategy may have broad implication in the epithelial solid tumor treatment. Funding Statement: This study is supported by grants of NCI (CA172106-01, Y.Z.) and NHLBI (HL127351-01A1, Y.Z.) and Fels Pilot Grant (S.H.). Declaration of Interests: All authors have no conflicting financial interests to declare. Ethics Approval Statement: Experimental protocols were approved by the Temple University's Committee on Use and Care of Animals. Whole blood was obtained from normal healthy donors, which was approved by the Institutional Review Board of Temple University.