A Cleveland Clinic-led team of scientists and physicians have discovered that the immune checkpoint protein VISTA can directly turn off tumor-fighting T-cells during immunotherapy and resist treatment.

The study, published in Science Immunology, explains that VISTA can bind to a protein called LRIG1 in T cells, which was previously only thought to promote bone and fat development.

When VISTA binds to LRIG1, the researchers found, LRIG1 sends signals that suppress T cell replication, survival and function. This interaction can happen between molecules on tumor cells and on T cells, molecules on healthy cells and T cells and even between molecules on the same T cell.

Their preclinical work suggests that blocking LRIG1 function can halt tumor growth in many cancers. In human melanoma and endometrial cancer, LRIG1 expression in tumor-associated T cells was correlated with resistance to immunotherapy.

VISTA modulates the immune responses of healthy cells to keep them from attacking our own bodies, protecting us from autoimmune issues. However, studies from a group led by Li Lily Wang, Ph.D., of Cleveland Clinic, have shown that during immunotherapy, VISTA impairs immune activation and prevents T cells from attacking cancer cells.

Pharmaceutical companies have tried to make therapeutics to block VISTA from working during immunotherapy. Success has been limited, because the field still does not know exactly how VISTA works.

The findings from this study follow another discovery from the laboratory of Dr. Wang, Translational Hematology and Oncology that showed VISTA indirectly suppresses our immune systems by promoting cells called myeloid-derived suppressor cells (MDSCs) that are well known to block T-cell function.

"Our two discoveries combined create a paradigm that explains how VISTA can act as a 'super villain' that uses many different weapons to impair antitumor responses during cancer treatments," says Dr. Wang. "This is an insight that drug developers need to consider if they want to boost treatment response rates to their full potential."

Immunotherapies and immune checkpoint therapies were a huge breakthrough in cancer treatments, providing hope for individuals affected by previously incurable cancers. But with response rates of only 20%–30% and high recurrence rates, Dr. Wang says there is still much room to improve.

"Studying the molecular aspect of how LRIG1 functions as VISTA's receptor on T cells can provide insights on how to successfully block VISTA and improve the clinical outcomes of the patients who don't respond to existing immune therapies," says lead first author Hieu Minh Ta, Ph.D.

This project was a collaboration between labs led by Dr. Wang and Timothy Chan, MD, Ph.D., Chair of Cleveland Clinic's Center for Immunotherapy & Precision Immuno-Oncology, Director of the Global Center for Immunotherapy and Sheikha Fatima bint Mubarak Endowed Chair in Immunotherapy. The paper has four co-first authors: postdoctoral fellows Dr. Ta and Dia Roy, Ph.D.; research associate Keman Zhang, Ph.D.; and project staff Tyler Alban, Ph.D.

The scientists worked closely with physicians including Brian Gastman, MD, Cleveland Clinic surgical oncologist, and Case Western Reserve University cancer pathologist Stefanie Avril, MD. Drs. Gastman and Avril provided the research team with melanoma and endometrial samples for studying the expression of LRIG1.

The results were striking. Patients who had been more resistant to immunotherapy had higher levels of LRIG1 in their tumor-fighting T cells.

"Our findings in human cancer samples inform and support the decision to go after LRIG1 as a potential drug target for new immune checkpoint therapies," says study co-first author Dia Roy, Ph.D.

The lab is now collaborating with many additional clinicians across Cleveland Clinic to learn more about how the VISTA/LRIG1 axis works in regulating immune responses against different cancer types including lung cancer and breast cancer. They expect that combining VISTA-specific inhibitors with existing immunotherapies may reduce resistance and recurrence and improve cancer patient survival.

More information: Hieu Ta et al, LRIG1 engages ligand VISTA and impairs tumor-specific CD8+ T cell responses, Science Immunology (2024). DOI: 10.1126/sciimmunol.adi7418. www.science.org/doi/10.1126/sciimmunol.adi7418