Engineering of Chimeric Antigen Receptor T Cells with integrin αEβ7 Results in Augmented Therapeutic Efficacy against E-cadherin positive tumor

Sun, H.; He, S.; Meng, L.; Wang, Y.; Zhang, H.; Liu, Y.; Wang, J.; Tao, M.; Barta, S. K.; Dulaimi, E.; Fung, H.; Issa, J.-P. J.; Zheng, L.-Z.; Zhang, Y.

doi:10.1101/727446

bioRxiv · 10.1101/727446

Engineering of Chimeric Antigen Receptor T Cells with integrin αEβ7 Results in Augmented Therapeutic Efficacy against E-cadherin positive tumor

Sun, H.·He, S.·Meng, L.·Wang, Y.·Zhang, H.·Liu, Y.·Wang, J.·Tao, M.·Barta, S. K.·Dulaimi, E.·Fung, H.·Issa, J.-P. J.·Zheng, L.-Z.·Zhang, Y.

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Abstract

Integrin E{beta}7 (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 anti-tumor 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.Il2R{gamma}cnull (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 E 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.\n\nHighlightsO_LICAR-T cells with 4-1BB costimulatory domain express reduced level of CD103\nC_LIO_LI4-1BB signaling antagonist TGF-{beta}1 induced CD103 expression\nC_LIO_LIEctopically expression of CD103 on CAR-T cells enhanced their anti-E-cadherin positive tumor capacity\nC_LI\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC=\"FIGDIR/small/727446v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (19K):\norg.highwire.dtl.DTLVardef@d32377org.highwire.dtl.DTLVardef@1bd841corg.highwire.dtl.DTLVardef@12c5c98org.highwire.dtl.DTLVardef@173382d_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract:\n\nGraphic Summary: The co-stimulatory molecule 4-1BB within the CAR protein potently suppresses CD103 expression. Engineering CAR-T cells with CD103 significantly enhances their capacity to proliferate and infiltrate into the solid tumor, leading to augmented anti-tumor immunity.\n\nC_FIG

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Sun, H., He, S., Meng, L., Wang, Y., Zhang, H., Liu, Y., Wang, J., Tao, M., Barta, S. K., Dulaimi, E., Fung, H., Issa, J.-P. J., Zheng, L.-Z., Zhang, Y.. 2019-08-06. Engineering of Chimeric Antigen Receptor T Cells with integrin αEβ7 Results in Augmented Therapeutic Efficacy against E-cadherin positive tumor. https://doi.org/10.1101/727446

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