Targeting Wnt10b in Melanoma Immune Surveillance
Abstract
This Idea Award proposal addresses the Focus Area of understanding the tumor microenvironment and meets the Fiscal Year 2020 (FY20) Challenge Statement descriptions. Background: Lymph nodes (LNs) are important immune organs in our body. They contain abundant immune cells that play important roles in fighting against cancer. The sentinel lymph node (SLN) is the first site to receive drainage from primary tumor. It is also the first site of immune recognition for patients with cutaneous melanoma, making it critically important in the shaping of subsequent adaptive immune responses. When melanoma cells metastasis to the SLN, we define those melanoma patients as node-positive SLN patients. They are classified as stage III. There is significant variation in disease recurrence among such patients. As such, a significant gap exists in our understanding of why there is such a wide disparity in outcomes among stage III melanoma patients and how/whether we can directly manipulate or modify anti-tumor immune responses in the SLN in order to reduce recurrence and improve survival. Scientific Objective and Rationale: In our initial studies, we found that Wnt10b was highly expressed in SLN in melanoma patients who later recurred versus those who did not. Wnt10b is one of the molecules in the Wnt signaling pathway that controls T-cell differentiation in SLN. We hypothesize that increased Wnt10b expression in SLN drives the differentiation of naive T cells to suppressive T cells (regulatory T cells, Tregs), thereby reducing anti-tumor immune responses and increasing the likelihood of recurrence in these patients. We further hypothesize that therapeutic targeting of Wnt10b in the SLN will inhibit the differentiation from naive T cells to suppressive T cells, restore anti-tumor immune responses, and reduce disease recurrence in SLN-positive patients. The objective of this application is to clarify how the highly expressed Wnt10b in SLN drives immune suppression and causes melanoma recurrence. The ultimate goal is to target Wnt10b to restore the immune response in order to reduce melanoma recurrence and improve survival. Specific Aims: We will test our hypothesis by pursuing the following two Specific Aims. Aim 1: Delineate the role of Wnt10b in driving T-cell differentiation and melanoma progression. Aim 2: Determine if Wnt10b functionally regulates melanoma disease progression in vivo. Ultimate Applicability of the Research: Melanoma has a rising incidence rate in both civilians and U.S. troops. This proposal aims at understanding the control of the immune cells to reduce recurrence and improve survival. Targeting on Wnt10b in melanoma surveillance might be a potential application to be translated to pre-clinical settings. This endeavor may lead to a marked reduction in the recurrence rate and increase the overall survival rate in those Service Members, their families, and other military beneficiaries who were diagnosed with malignant melanoma.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110735
Entities
People
- Kelly M. McMasters
Organizations
- United States Army
- University of Louisville