Back in 2011, Cleveland Clinic researchers reported that the checkpoint protein V-domain immunoglobulin suppressor of T cell activation (VISTA) inhibited the T cell response when overexpressed on tumor cells and speculated that it would be a good cancer immunotherapy target (1). Over the next decade, the scientists focused on identifying VISTA's binding partners and signaling mechanisms.

LRIG1 single-handedly seems to be having a major effect if you knock it out,
– Li Lily Wang, Cleveland Clinic

In a new study, those same scientists now reported that the inhibitory receptor leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) inhibits T cell proliferation, survival, and effector function when bound to VISTA (2). The findings, published in Science Immunology, introduce a new target in the fight against cancer and offer a potential explanation for immunotherapy resistance or cancer recurrence.

“Identifying new immune checkpoints that also affect T cell activation is important so they can be targeted and lead to the development of new therapeutic strategies,” said Lionel Apetoh, an immunologist at Indiana University, who was not involved in the study.

During their search for VISTA’s binding partners, the team discovered LRIG1, a protein expressed on stem cells in both healthy and cancerous tissues (3). “But just because the protein binds doesn't mean it has any relevant function,” said Li Lily Wang, an immunologist at the Cleveland Clinic and study coauthor. “That's when the project started looking more and more promising because we found out that if we engaged LRIG1, T cells get shut down and the tumor gets controlled better because the tumor-reactive T cell response is enhanced.”  

Other scientists had identified other VISTA binding partners but none that directly caused T cell functional outcomes. “LRIG1 single handedly seems to be having a major effect if you knock it out,” said Wang.

The team confirmed LRIG1’s inhibitory role in in vitro and in vivo experiments, and in patient tumor samples. Compared to normal T cells, stimulated cultured T cells without LRIG1 or VISTA showed increased T cell receptor signaling. Stimulated T cells lacking LRIG1 showed greater expansion, higher cytokine production, and reduced cell death.

Within tumors overexpressing VISTA, wildtype T cells were significantly diminished, while T cells lacking LRIG1 were resistant to VISTA-mediated suppression. LRIG1 knockout mice had increased CD8⁺ tumor infiltrating lymphocyte expansion and improved effector function along with delayed tumor growth compared to wildtype animals.

In melanoma patients treated with immune checkpoint inhibitors, a significantly higher proportion of CD8⁺ tumor infiltrating lymphocytes expressed LRIG1 in those who did not respond to therapy compared to those who did. 

In future work, Wang’s group plans to study whether LRIG1 binds to ligands other than VISTA and the exact downstream signaling mechanisms of LRIG1. They also plan to investigate whether one or more therapeutic reagents blocking the VISTA-LRIG1 axis show effective outcomes in tumor models. 

“We have a relatively strong case to argue for this axis to be a very significant regulator of anti-tumor immunity,” Wang said. “There are a lot more follow-up studies to be done, and we're very excited about this direction.”

References 

1. Wang, L. et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med  208, 577–592 (2011).
2. Ta, H. M. et al. LRIG1 engages ligand VISTA and impairs tumor-specific CD8+ T cell responses. Sci Immunol  9, eadi7418 (2024).
3. Wang, Y., Poulin, E.J. & Coffey, R.J. LRIG1 is a triple threat: ERBB negative regulator, intestinal stem cell marker and tumour suppressor. Br J Cancer  108, 1765–1770 (2013).