Targeting Regnase-1 unleashes CAR T cell antitumor activity for osteosarcoma and creates a proinflammatory tumor microenvironment
Adeshakin, A. O.; Shi, H.; Perry, S. S.; Sheppard, H.; Nguyen, P.; Sun, X.; Zhou, P.; Metais, J.-Y.; Cunningham, T.; KC, A.; Tian, L.; Peche, V.; Prater, M. S.; Langfitt, D. M.; Pruett-Miller, S. M.; Yustein, J. T.; Krenciute, G.; DeRenzo, C.; Chi, H.; Gottschalk, S.
Show abstract
Negative regulators of T cell function represent promising targets to enhance the intrinsic antitumor activity of CAR T cells against solid tumors. However, the endogenous immune ecosystem in solid tumors often represents an immunosuppressive therapeutic barrier to CAR T cell therapy, and it is currently unknown whether deletion of negative regulators in CAR T cells reshapes the endogenous immune landscape. To address this knowledge gap, we developed CAR T cells targeting B7-H3 in immune-competent osteosarcoma models and evaluated the intrinsic and extrinsic effects of deleting a potent negative regulator called Regnase-1 (Reg-1). Deletion of Reg-1 not only improved the effector function of B7-H3-CAR T cells but also endowed them with the ability to create a proinflammatory landscape characterized by an influx of IFN{gamma}-producing endogenous T cells and NK cells and a reduction of inhibitory myeloid cells, including M2 macrophages. Thus, deleting negative regulators in CAR T cells enforces a non-cell-autonomous state by creating a proinflammatory tumor microenvironment.
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