Multidimensional Reversal of T-Cell Exhaustion in Melanoma
Abstract
Focus Area The proposed studies address Fiscal Year 2019 (FY19) Melanoma Research Program (MRP) topic, Therapeutic Prevention: Interruption of Disease Progression, Recurrence. The FY19 MRP challenge to the research community is to identify novel ways to initiate or enhance prevention of melanomagenesis throughout the disease, including the prevention of metastasis. Our research has direct applicability to the prevention of disease progression and metastasis and could dramatically reduce the number of patients whose disease progresses to metastatic melanoma. Scientific Objective and Rationale New advances in immunotherapy have yielded tremendous optimism that metastatic melanoma, an aggressive and fatal cancer, can one day be cured in the majority of patients. Metastatic melanoma, the deadliest skin cancer, develops when the sun’s ultraviolet radiation causes mutations in skin melanocytes, leading to their conversion to cancer cells that escape the immune system. US military personnel have elevated disease incidence and poorer prognosis than the general population because of the broad exposure to outdoor work-related activities. This is particularly true for those individuals who have recently or are currently serving in areas such as Afghanistan and Iraq or have served in Southwest Asia and the Western Pacific, primarily because of high levels of occupational sun exposure in these geographical areas. Melanoma tumor eradication depends on responses by CD8 T cells. These tumors can evade the immune system by inhibiting T cell responses. Although immunotherapies that block PD-1/PD-L1 and CTLA-4 can greatly improve antitumor responses and are now the standard of care, their efficacy individually or in combination is limited, and few patients experience long-term responses without tumor reoccurrence. The goal of this project is to develop a novel strategy to significantly improve responses in patients with metastatic melanoma to immunotherapy (currently at about 20%) by targeting a novel protein on T cells, designated PSGL-1. We hypothesize that PSGL-1 controls a fundamental regulatory program of genes that prevent T cells from eradicating melanoma tumors and dramatically limits the efficacy of current therapies. As such, we propose that blocking PSGL-1 can subvert diverse pathways of T cell suppression simultaneously, thereby avoiding the need to target multiple inhibitory receptors by combination immunotherapies. We propose novel, fundamental, and translational studies of T cell responses to melanoma with targeting of PSGL-1 to relieve multiple aspects of immune inhibition that we believe have the potential to be a significant advance for achieving durable responses for most melanoma patients. The Aims of this project are: (1) To define the genetic programs in T cells that are regulated by PSGL-1 and promote T cell loss of function or exhaustion in preclinical models of melanoma and in melanoma patient samples; and (2) To assess whether blocking PSGL-1 can reverse T cell exhaustion and promote protection against tumor reoccurrence. Innovation The proposed research has significant potential to help patients with metastatic melanoma who have failed current immunotherapies by offering a new treatment with the potential to more broadly reverse inhibition of the T cell immune response and thereby, improve patient survival. Realizing this potential will improve the lives of not only patients, but also their families. This will be significant for those currently serving in the military and their families or Veterans, since the incidence of this cancer is higher and the prognosis is poorer in this population in the United States. Our studies have the potential to advance the field of melanoma research. In light of new findings that T cell exhaustion is coordinately regulated by a network of genes, our studies will determine if PSGL-1 acts to regulate this network. If so, releasing the break from this IR has the far-rea
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010324
Entities
People
- Linda Bradley
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army