Investigating the Role of a Novel Dendritic Cell Subset Within Sentinel Lymph Node Tissues in Immune Evasion and Melanomagenesis
Abstract
This project will address the Fiscal Year 2020 (FY20) Melanoma Research Program (MRP) Focus Area entitled, “Understanding the Melanoma Microenvironment - Regional Nodes” by examining the role of a newly identified suppressive cell type residing within draining lymph node tissues in the process of melanoma progression and metastasis. This work further addresses the FY20 MRP Challenge Statement as an improved understanding of the development and function of this suppressive immune cell type within nearby lymph node tissues is expected to lead to the design and development of novel therapeutic strategies capable of preventing melanoma micrometastases. The first objective of this proposed project will be to investigate the role of a novel immune cell population within draining lymph node tissues in suppressing melanoma immunity and in contributing to melanoma metastasis. The second objective will be to examine the underlying pathways that drive the development and function of this novel immune cell population and to explore whether blocking these pathways suppress melanoma progression. Finally, the third objective will be to determine whether this same immune cell population resides within human lymph node tissue specimens and whether this immune cell type impacts melanoma recurrence in patients. The immune cell population of interest in this proposed project is the dendritic cell, an antigen-presenting cell within our immune system that typically plays a critical role in the activation of T cells and the direction of cellular immune responses to cancers. During the course of melanoma progression, a portion of this dendritic cell population becomes immunosuppressive and contributes to cancer progression. It is not entirely understood how this process occurs. One of the challenges associated with this research is that no specific marker of immunosuppressive dendritic cell populations has been identified. However, we have recently discovered a novel population of dendritic cells that can be identified with a specific marker that we believe plays an important role in mediating immune evasion and promoting melanoma progression. As a result, we are now able to isolate this immunosuppressive dendritic cell population for the first time, allowing for a more in-depth study of how this immunosuppressive dendritic cell population contributes to melanoma metastasis. Our data to date indicates that these dendritic cells suppress T cell activation while also accumulating within draining lymph node tissues as melanomas progress. By understanding those pathways responsible for driving the development and the suppressive functionality of these dendritic cells in melanoma, we expect this work to lead to the development of novel immunotherapeutic strategies capable of inhibiting the progression of melanoma metastases and improving the management of melanoma patients. In order to achieve these objectives, we will utilize a genetically engineered model of melanoma that we have previously shown to accurately recapitulate the physiology of human melanoma. This mouse model will be further paired with lymph node tissue specimens from human melanoma patients to complete the proposed studies. At the conclusion of this work, we expect to have validation that this novel dendritic cell population suppresses immune responses to melanoma and that this ability empowers these dendritic cells to be critical regulators of melanoma metastases. Additional studies will further identify a key underlying metabolic pathway important for the functionality of this dendritic cell population as well as data to support the therapeutic targeting of this metabolic pathway as a strategy for reducing the risk of melanoma recurrence and metastasis. We also expect these studies to provide initial data toward the use of this specific dendritic cell marker as a lymph node tissue biomarker for identifying those melanomas at increased risk of progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110847
Entities
People
- Brent A Hanks
Organizations
- Duke University
- United States Army