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

Sci Immunol. 2024 May 17;9(95):eadi7418. doi: 10.1126/sciimmunol.adi7418. Epub 2024 May 17.

Abstract

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+ CD62Lhi PD-1low) 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.

MeSH terms

  • Animals
  • B7 Antigens* / genetics
  • B7 Antigens* / immunology
  • CD8-Positive T-Lymphocytes* / immunology
  • Cell Line, Tumor
  • Humans
  • Membrane Glycoproteins* / genetics
  • Membrane Glycoproteins* / immunology
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins
  • Tumor Microenvironment* / immunology

Substances

  • B7 Antigens
  • LRIG1 protein, human
  • Lrig1 protein, mouse
  • Membrane Glycoproteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • VSIR protein, human
  • Vsir protein, mouse