A group of scientists and doctors have made a discovery about the immune checkpoint protein VISTA. They found that VISTA can switch off T-cells that fight tumors during immunotherapy. This makes the treatment less effective. The study shows that VISTA can connect to a protein called LRIG1 in T-cells. LRIG1 was previously believed to only help with bone and fat development. But when VISTA connects to LRIG1, it sends signals that stop T-cells from replicating, surviving, and functioning properly. This connection can happen between molecules on tumor cells and T-cells, molecules on healthy cells and T-cells, and even between molecules on the same T-cell. <p id=”first” class=”l rnrnA team of scientists and physicians at the Cleveland Clinic has made a discovery about the immune checkpoint protein VISTA. They found that VISTA can directly shut down T-cells that fight tumors during immunotherapy, making the treatment less effective. The study, which was published in Science Immunology, reveals that VISTA can connect with a protein called LRIG1 in T cells. LRIG1 was previously believed to only play a role in bone and fat development. Once VISTA binds to LRIG1, the researchers discovered that LRIG1 sends signals that inhibit T cell replication, survival, and function. This interaction can occur between molecules on tumor cells and on T cells, as well as between molecules on healthy cells.The interactions between LRIG1 and VISTA can have significant effects on the immune response, especially in the context of cancer. LRIG1 plays a role in inhibiting the growth of tumors, and its expression in T cells has been linked to resistance to immunotherapy in melanoma and endometrial cancer. On the other hand, VISTA is involved in regulating immune responses to prevent autoimmune issues, but it can also hinder the activation of T cells during immunotherapy, thus hindering their ability to attack cancer cells. This research has implications for the development of targeted therapies to modulate these interactions for improved cancer treatment outcomes.Pharmaceutical companies have attempted to develop drugs to inhibit the effects of VISTA during immunotherapy, but their success has been limited due to a lack of understanding about how VISTA functions.
This study’s findings build upon a previous discovery by Dr. Wang’s laboratory, which revealed that VISTA indirectly suppresses the immune system by promoting myeloid-derived suppressor cells (MDSCs), known for their ability to block T-cell function.
These two discoveries together provide a framework for understanding how VISTA can act as a “super villain,” utilizing various mechanisms to hinder the immune response.Humor 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 cl rnrnHumor responses during cancer treatments,” according to Dr. Wang. It’s a key insight for drug developers looking to maximize treatment response rates. Immunotherapies and immune checkpoint therapies have offered hope for those with previously untreatable cancers. But with response rates of just 20% — 30% and high recurrence rates, there is still significant room for improvement, Dr. Wang says. Understanding the molecular function of LRIG1 as VISTA’s receptor on T cells could provide valuable insights into effectively blocking VISTA and enhancing the clearance of cancer cells.The primary focus of the study was on the initial outcomes of patients who do not respond to current immune therapies,” explained lead author Hieu Minh Ta, PhD.
This research was a joint effort between Dr. Wang’s and Timothy Chan, MD, PhD’s laboratories. Dr. Chan is the 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, PhD; research associate Keman Zhang, PhD; and project staff Tyler Alban, PhD.
The researchers collaborated closely with physiThe research team, led by Drs. Brian Gastman and Stefanie Avril, received melanoma and endometrial samples to study LRIG1 expression. They found that patients resistant to immunotherapy had higher LRIG1 levels in their tumor-fighting T cells. “Our findings suggest that targeting LRIG1 could be a potential drug target for new immune checkpoint therapies,” says co-first author Dia Roy, PhD.
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