The inhibitory VISTA LRIG1 axis impairs the persistence and function of CAR T cells

Background: Chimeric antigen receptor (CAR) T cell therapy has transformed lymphoma treatment; however, 40 to 60 percent of responding patients relapse due to poor CART persistence. Leucine Rich Repeats and Immunoglobulin Like Domains 1 LRIG1 is known for maintaining stem cell quiescence. Its role in T cell biology was recently unveiled with the discovery that LRIG1 acts as an inhibitory receptor for V domain Immunoglobulin Suppressor of T cell Activation VISTA. Our studies suggest that LRIG1 is expressed on activated T cells inhibiting TCR signaling upon engaging VISTA. Methods & Results: This study addresses the hypothesis that VISTA LRIG1 axis limits CAR T cell durability and function. To investigate this, we generated LRIG1 knockdown human CAR T cells alongside wildtype controls. In coculture with Raji target cells, WT CART cells exhibited antigen density dependent upregulation of LRIG1, implicating LRIG1 as a regulator of CART functional capacity. Consistent with this, LRIG1 deficient CD19scFV human CAR T cells showed better efficacy in controlling Raji lymphoma both in vitro and in vivo. To complement findings from immune deficient NSG mice models, we evaluated the function of LRIG1 in CAR T cells in murine models. We found that LRIG1 ablation improved CAR T cell persistence and led to long term tumor regression in B cell lymphoma and melanoma murine models. Conclusions: LRIG1 functions as a previously unrecognized T cell checkpoint that engages VISTA to limit CART persistence and function. Targeting this LRIG1 VISTA axis may enhance CART efficacy and merits further investigation.