Modulation of Tumor Microenvironment to Hinder Cancer Progression and Therapeutic Resistance
Abstract
The proposed project addresses Fiscal Year 2021 (FY21) Melanoma Research Program (MRP) Focus Areas of (1) Identify how the tumor microenvironment impact tumor initiation, response to therapy, and progression, and (2) Delineate the molecular pathways, tumor microenvironment, immune response that influence metastatic spread, recurrence and/or dormancy. It is responsive to the program’s goals and the FY21 MRP Challenge Statement of redefining prevention to include the entire melanomagenesis process and for all variants of melanoma. Due to prolonged sun exposure and lack of sufficient protection from the sun and other hazardous conditions during active duty, members of the Army, Air Force, Navy, Marine Corps, Coast Guard, and the Veteran population suffer a further elevated rate of skin cancer. Melanoma is the most difficult to treat and the most deadly form of skin cancer. Recent advances in immunotherapies and oncogene-targeted small molecular inhibitors have expanded treatment options. However, over 60% of melanoma patients show no response to immunotherapy, and the benefit of oncogene inhibitors is generally limited to a few months of duration owing to the rapid development of resistance. Additionally, rare subtypes of melanoma such as those arising on the hands, feet, ears, or nose (known as acral melanomas) often lack targetable oncogenic mutations; these melanomas are also less likely to benefit from current immunotherapy. Therefore, a critical need exists for novel treatments. A critical barrier to prevention of melanoma progression and resistance to therapy is inadequate immunosurveillance within the tumor microenvironment (TME). Such an immune deficient TME is often marked by a disproportionally high number of immune suppressive regulatory T-cells (Tregs) and a low number of cytotoxic effector T-cells (CTLs). The objective of this study is to explore new opportunities to decrease pro-tumor Treg activities and increase anti-tumor CTL activities. Our strategy is based on the observation that UBE2N, a ubiquitin conjugase, is crucial for Treg maintenance and prevention of CTL expansion. In addition, our preliminary studies show that UBE2N acts not only in cancer cells to promote proliferation but also in TME cells to support melanoma growth. The goal of this study is to characterize the function of UBE2N in TME immune cells and develop a clinically applicable strategy to increase CTL/Treg ratio through strategic targeting of UBE2N in pro-tumor immune cells. This work will uncover new knowledge about how immune cells are regulated in TME and how such regulatory signals can be harnessed to enhance immunotherapy. Such knowledge will provide insights to the design of new prevention and treatment strategies for cutaneous melanoma and other rare types of melanoma. In addition, the possibility of amplifying CTL through local or ex vivo treatments of tumor organoids and peripheral blood cells will expand opportunities for therapeutic targeting and decrease side effects associated with systemic drug delivery. Upon completion, results of this study will pave the way for a potential clinical translation of a new treatment to benefit melanoma patients of active-duty Service Members of the Army, Air Force, Navy, Marine Corps, and Coast Guard, as well as Veterans and the nonmilitary population.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211061
Entities
People
- Yunyan Zhang
Organizations
- Duke University
- United States Army