Targeting a Novel T-Cell Inhibitory Receptor and Develop Novel Immunoprevention Approaches for Melanoma
Abstract
Personnel: Since establishing my independent laboratory in 2012, I have maintained an active research program with an overall focus in understanding the immunoregulatory mechanisms and developing novel therapeutics for cancer immunotherapy. My laboratory has been funded by National Institutes of Health/National Cancer Institute, Department of Defense, and research foundations including Melanoma Research Foundation, Melanoma Research Alliance, American Institute of Cancer Research, and American Cancer Society. We have a long-standing research interest in melanoma and have established VISTA as a relevant immune checkpoint receptor (ICR) for melanoma immuontherapy. One of the most challenging aspects of VISTA biology is the lack of a defined receptor and signaling mechanisms. This current proposal is based on many years of commitment and efforts of my team in identifying such a receptor, which may be a key discovery that could advance the field of immunoprevention and immuontherapy for melanoma. Focus Area: This proposal aims to establish a novel immunoprevention approach by targeting a novel ICR. Thus, this proposal responds to Fiscal Year 2021 (FY21) Melanoma Research Program (MRP) Challenge, to redefine prevention… impede the initiation and progression of primary melanoma. We will addresses the following FY21 MRP Focus Areas, including Identify how the tumor microenvironment (e.g., immune) impact tumor initiation, response to therapy, progression… Identify biological determinants to differentiate patient populations... Delineate the molecular pathways, tumor microenvironment, immune response that influence metastatic spread, recurrence. Objectives and Rationale: The concept of cancer immunoprevention is to enhance immunosurveillance during early stages of carcinogenesis and drive clearance of nascent tumors prior to immune escape. Inhibitors targeting ICRs including CTLA4 and PD-1 are breakthrough therapies for late-stage melanoma, but their utility as immunoprevention agents is limited by significant immune-related adverse events and presumably low responsive rate. Thus, it remains an urgent need to determine if additional ICRs are suitable targets of immunoprevention for melanoma. Our preliminary studies have identified a novel ICR that interacts with another well-established immune checkpoint protein VISTA. Genetic deletion of this receptor enhanced T cell responses and suppressed tumor growth in a preclinical melanoma model. These preliminary results have led to the overall hypothesis that this novel ICR axis impairs T cell-mediated immunosurveillance and promotes progression and recurrence of melanoma. The main objective of this proposal is to establish the role of this novel ICR in promoting immune evasion in melanoma. A second objective is to develop inhibitors that will block the binding and function of this receptor. A third objective is to determine the safety and effects of such inhibitors in augmenting immunosurveillance and preventing melanoma progression and recurrence in preclinical models. A fourth objective is to determine if the expression of this ICR in tumor-associated lymphocytes and the immune gene signatures associated with this receptor are correlated with progression and recurrence of melanoma. Applicability of the Research and Military Relevance: Melanoma progression is not only influenced by cell-autonomous oncogenic pathways, but also controlled by immune-mediated mechanisms, such as tumor-specific killing by cytotoxic lymphocytes. There is an urgent need to develop effective and safe immunoprevention approaches that will prevent immune-evasion in high-risk melanoma patients. While the existing immune checkpoint inhibitors may not be suitable for immunoprevention, our proposed studies will develop inhibitors targeting a new ICR axis and test the efficacy of such inhibitors in both primary and secondary prevention settings in preclinical melanoma models. Upon successful completion of thi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210707
Entities
People
- Li Wang
Organizations
- Cleveland Clinic
- United States Army