GRP78-CAR T cell effector function against solid and brain tumors is controlled by GRP78 expression on T cells

Abstract

Lack of targetable antigens is a key limitation for developing successful Tcell-based immunotherapies. Members of the unfolded protein response (UPR) represent ideal immunotherapy targets because the UPR regulates the ability of cancer cells to resist cell death, sustain proliferation, and metastasize. Glucose-regulated protein 78 (GRP78) is a key UPR regulator that is overexpressed and translocated to the cell surface of a wide variety of cancers in response to elevated endoplasmic reticulum (ER) stress. We show that GRP78 is highly expressed on the cell surface of multiple solid and brain tumors, making cell surface GRP78 a promising chimeric antigen receptor (CAR) Tcell target. We demonstrate that GRP78-CAR Tcells can recognize and kill GRP78+ brain and solid tumors invitro and invivo. Additionally, our findings demonstrate that GRP78 is upregulated on CAR Tcells upon Tcell activation; however, this expression is tumor-cell-line specific and results in heterogeneous GRP78-CAR Tcell therapeutic response.