LRIG1 engages ligand VISTA and impairs tumor-specific CD8+ T cell responses.

Immune checkpoint blockade is a promising approach to activate antitumor immunity and improve the survival of patients with cancer. V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint target; however, the downstream signaling mechanisms are elusive. Here, we identify leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a VISTA binding partner, which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell–specific LRIG1 deletion developed superior antitumor responses because of expansion of tumor-specific cytotoxic T lymphocytes (CTLs) with increased effector function and survival. Sustained tumor control was associated with a reduction of quiescent CTLs (TCF1⁺ CD62L^hi PD-1^low) and a reciprocal increase in progenitor and memory-like CTLs (TCF1⁺ PD-1⁺). In patients with melanoma, elevated LRIG1 expression on tumor-infiltrating CD8⁺ CTLs correlated with resistance to immunotherapies. These results delineate the role of LRIG1 as an inhibitory immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy. Editor's summary: The negative checkpoint regulator VISTA has emerged as a promising target for cancer immunotherapy. VISTA plays an important role in maintaining T cell quiescence; however, the molecular mechanisms through which VISTA regulates antitumor immunity are not well defined. In this study, Ta et al. identified LRIG1 as a VISTA-binding partner and co-inhibitory receptor. VISTA engagement by LRIG1 impaired murine antitumor immunity by promoting quiescence in tumor-specific CD8 T cells and limited the abundance of progenitor and memory-like cells with the ability to differentiate into effector T cells. In patients with melanoma, expression of LRIG1 on tumor-infiltrating lymphocytes correlated with resistance to immunotherapy. Together, these findings suggest that selectively inhibiting VISTA/LRIG1 may be an effective cancer immunotherapy. —Hannah Isles [ABSTRACT FROM AUTHOR]