Single-Cell Analysis of LAG3 Checkpoint Inhibition in Metastatic Uveal Melanoma
Abstract
The most common cause of death from cancer is spread or metastasis to vital organs. Uveal melanoma (UM) is a highly aggressive eye cancer that metastasizes in up to half of patients, with a strong predilection for the liver. UM has a tendency to undergo early micrometastasis prior to treatment of the primary tumor, with later development of overt metastatic disease. However, the molecular mechanisms by which UM metastasizes remain poorly understood, and there are no cancer drugs available that are effective in treating metastatic UM. Consequently, there has been no measurable improvement in survival over the past half century. The overall objective of our UM research program is to improve patient survival rates by identifying effective therapies based on new mechanistic insights into the tumor microenvironment. In our study published in Nature Communications earlier this year, we used cutting edge single-cell RNA-sequencing (scRNA-seq) technology for the first time in UM to discover that the predominant checkpoint marker on CD8+ T cells is LAG3, rather than the widely studied CTLA4 and PD1. This finding could explain why PD1- and CTLA4-directed checkpoint immunotherapy has not effective for this cancer. Based on this discovery, we have entered into an agreement with Bristol Myers Squibb to test the efficacy of their LAG3 inhibitor in patients with metastatic UM. The proposed DOD Melanoma Research Translational Research Award will provide for the analysis of correlative biomarkers, which will be critically important to gain as much insights as possible into the tumor microenvironment, tumor responsiveness, and therapeutic prevention. This will be the first comprehensive analysis of the tumor microenvironment and circulating immune response to checkpoint immunotherapy ever performed in UM. We anticipate that the results of this work will lead to a paradigm shift in the management of metastatic UM. This proposal addresses several Fiscal Year 2020 (FY20) Melanoma Research Program (MRP) Focus Areas, including: (1) Understanding the Tumor Microenvironment, (2) Therapeutic Prevention, and (3) Rare Melanomas. Assessing tumor microenvironment and circular immune response to as a way to evaluate a checkpoint inhibitor as a way to stop the progression of metastatic disease aligns with the FY20 MRP Challenge Statement, especially in rare melanoma subtypes. With the use of a checkpoint inhibitor as a possible way to stop the spread metastasis disease in UM patients, especially for those BAP1-mutant patients who are at higher risk for metastasis. This proposal could have a direct impact on patients with cancers harboring BAP1 mutations, particularly those with melanomas, mesotheliomas, and kidney cancers harboring BAP1 mutations. The proposal has the potential for direct clinical application and benefit through stopping the metastatic spread to distant organs. The knowledge gained during this research could have a far-reaching impact on similar research on other tumor suppressor genes and cancer types. This could have a particularly profound impact on military health, active-duty Service Members, their families, and other military beneficiaries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110944
Entities
People
- J William Harbour
Organizations
- United States Army
- University of Miami