Study reveals VISTA inhibits T-cell function in immunotherapy

A team of researchers and medical professionals has uncovered a crucial mechanism by which the immune checkpoint protein VISTA can deactivate tumor-fighting T-cells during immunotherapy, thereby resisting treatment. This discovery highlights the role of VISTA in binding to LRIG1, a protein in T cells previously known for its role in bone and fat development. Upon binding, LRIG1 signals the suppression of T cell replication, survival, and function. Such interactions can take place between tumor cells and T cells, healthy cells and T cells, and even within the same T cell.

Conducted by a team from the Cleveland Clinic, this study, published in Science Immunology, suggests that blocking the function of LRIG1 could inhibit tumor growth across various cancers. The research found that in cases of human melanoma and endometrial cancer, the presence of LRIG1 in tumor-associated T cells was linked to resistance against immunotherapy.

VISTA normally regulates immune responses to prevent autoimmune diseases by keeping healthy cells from attacking the body's own tissues. However, research led by Dr. Li Lily Wang at Cleveland Clinic revealed that during immunotherapy, VISTA hinders immune activation, preventing T cells from attacking cancer cells effectively. Pharmaceutical companies have endeavored to develop treatments to inhibit VISTA’s function during immunotherapy, but progress has been slow due to incomplete understanding of VISTA’s mechanisms.

This study builds on previous work from Dr. Wang’s laboratory, which demonstrated that VISTA indirectly weakens the immune system by promoting myeloid-derived suppressor cells (MDSCs), known for their role in obstructing T-cell function. "These two discoveries together create a new understanding of VISTA's role as a 'super villain' deploying various methods to undermine antitumor responses during cancer treatment," said Dr. Wang. This insight is critical for drug developers aiming to enhance treatment efficacy.

Immunotherapies and immune checkpoint therapies marked significant advances in cancer treatments, offering hope to patients with previously untreatable cancers. Yet, with success rates hovering between 20% and 30% and high rates of recurrence, Dr. Wang emphasizes the need for continued improvement. "Understanding the molecular details of how LRIG1 functions as VISTA's receptor on T cells could provide valuable insights for effectively blocking VISTA and improving the clinical outcomes for patients who do not respond to current immune therapies," stated lead author Dr. Hieu Minh Ta.

This study was a collaborative effort between the labs of Dr. Wang and Dr. Timothy Chan, Chair of Cleveland Clinic's Center for Immunotherapy & Precision Immuno-Oncology, and Director of the Global Center for Immunotherapy. The paper includes contributions from four co-first authors: postdoctoral fellows Dr. Ta and Dr. Dia Roy, research associate Dr. Keman Zhang, and project staff Dr. Tyler Alban.

Additionally, the team collaborated with clinical experts such as Dr. Brian Gastman, a surgical oncologist at the Cleveland Clinic, and Dr. Stefanie Avril, a cancer pathologist at Case Western Reserve University. Drs. Gastman and Avril provided melanoma and endometrial tissue samples for studying LRIG1 expression.

The findings were remarkable, showing that patients with higher levels of LRIG1 in their tumor-fighting T cells were more resistant to immunotherapy. "Our results from human cancer samples support targeting LRIG1 as a potential focus for new immune checkpoint therapies," remarked Dr. Dia Roy.

These discoveries underscore the potential for novel therapeutic strategies targeting LRIG1 to improve the effectiveness of immunotherapy in cancer treatment, paving the way for more successful interventions in the future.