Neuropilin-1 expression by solid tumors impairs CAR T cell function

Abstract

Neuropilin-1 (NRP-1) is a versatile transmembrane protein expressed in numerous cell types and tissues, both in health and in disease. In particular, it is expressed by activated T cells, where it has been shown to play an inhibitory role, dampening their response to tumor cells. Chimeric antigen receptor (CAR) T cells have had considerable success in treating cancers such as B cell leukemias, but face several obstacles in the treatment of solid tumors. We hypothesized that NRP-1 may contribute to dampening CAR T cell responses to cancer. While NRP-1 blockade either through neutralizing antibodies or through CRISPR/Cas9-mediated deletion did not improve CAR T cell cytotoxic activity in an in vitro solid tumor model, NRP-1 was found to have a protective effect against CAR T cells when expressed by the tumor cells, in line with previous literature implicating NRP-1 as a pro-tumor factor involved in their growth and invasiveness. We found that NRP-1 was transferred from target cells to CAR T cells via trogocytosis, i.e. the "nibbling" and subsequent display of membrane proteins from one cell by another. CD19, the target antigen in this model, was also transferred to CAR T cells, raising interesting questions about trogocytosis as a marker for effective tumor cell killing through direct interaction. On the contrary, trogocytosis may impede effective CAR T function by promoting fratricide due to their display of target antigen. While no conclusive mechanisms for NRP-1 activity were found, several avenues of research have been opened up to further our understanding of the multifaceted roles of NRP-1 in CAR T cell activity and interactions with their targets.