Modulation of T-Cell Receptor-Mediated Intratumoral Antigen Recognition
Abstract
It has long been recognized that the immune system plays a central role in controlling the growth of melanoma tumors. Studies of the function of immune cells within tumors have led to a better understanding of the relationship of the tumor to its host and the formulation of strategies for harnessing the immune system to combat cancer. The advent of therapies that enhance the immune response to melanoma has revolutionized treatment approaches and dramatically improved the long-term prospects for patients with metastatic disease. However, a substantial proportion of patients with metastatic melanoma are not responsive to current immunotherapy approaches, and a broad aim of the melanoma research community is to determine the mechanisms that suppress immune cell function in the tumor environment and resistance to immune-based therapies. We propose that the ability of immune cells to recognize tumor cells is impaired within actively growing tumors, creating a barrier to immune cell activation and function that must be overcome before they can be recruited into the anti-tumor immune response. We seek to define the parameters that control the ability of immune cells to recognize tumors, and determine how those parameters can be modulated to enhance the anti-tumor immune response. This proposal is most directly responsive to the FY21 MRP Focus Area, Identify how the tumor microenvironment (e.g., stromal, immune, microbiome) impact tumor initiation, response to therapy, progression, and dormancy. The Principal Investigator, Dr. Matthew Williams, has extensive experience studying immune responses to viruses, bacteria, and melanoma. His particular focus has been to understand the biology of T cells, a white blood cell subset that is central to the adaptive immune response. In recent years he has demonstrated that the ability of T cells to respond to melanoma is controlled by their ability to recognize tumors and generate functional responses. He has additionally identified pathways that can be targeted to rescue the ability of T cells to recognize tumors and eradicate them. The major goals of this proposal are to: (1) Better understand how the ability of T cells to recognize tumors evolves during tumor growth, (2) Define changes in the ability of T cells to recognize tumors in response to immune-based therapies, and (3) Identify and characterize pathways that prevent the ability of T cells to recognize tumors. Over the short term, our studies will greatly enhance our understanding of how the ability of T cells to recognize tumors is restrained, and set the stage for identifying and validating therapeutic targets to enhance their function. Over the long term, we propose that enhancing the ability of poorly reactive immune cells to recognize tumors and exert anti-tumor function will lead to the development of treatment approaches that complement existing immune-based therapies and expand the pool of melanoma patients that are able to benefit.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210776
Entities
People
- Matthew Williams
Organizations
- United States Army
- University of Utah