Understanding the Role of Immature Myeloid Cells in Early Melanoma Establishment
Abstract
Fiscal Year 2021 (FY21) Melanoma Research Program (MRP) Focus Area: Identify how the tumor microenvironment (e.g., stromal, immune, microbiome) impact tumor initiation, response to therapy, progression, and dormancy. All melanomas originate from melanocytes, but very few melanocytes will eventually transform to become melanomas. Similarly, not all melanoma cell lines grown in the laboratory can form tumors when injected into animal models, and those that can frequently require the transfer of tens – if not hundreds – of thousands of cells to achieve the establishment of a tumor mass. These observations suggest that melanomas establish and grow as a consequence of local events that support melanoma growth and prevent destruction by the immune system. This project addresses the FY21 MRP Challenge Statement by examining the role of immature immune cells in helping melanoma cells to form into tumors. These immature immune cells, known as immature myeloid cells, would normally mature into immune cells that help us fight against pathogens such as bacteria. In cancer patients with established tumors, immature myeloid cells do the opposite by secreting growth factors and developing into suppressor cells with a potent ability to stop our immune system from controlling cancer. The precise mechanisms that drive these processes remain unclear. Evidence from the clinic indicates that melanoma patients have increased numbers of immature myeloid cells in their skin. Furthermore, evidence from the laboratory has shown that the transformation of patient-blood-derived immature myeloid cells into suppressor cells can occur when melanoma cells and immature myeloid cells interact with one another. These simple observations led to the question that underpins this grant application – do melanomas form and grow because of early interactions between melanoma cells and immature myeloid cells? Understanding more about these interactions in animal models will help to answer this question. Recent technological advances are shedding light on the interactions between cells in tumors. This entails spatial analysis of genes and proteins in fixed tumor tissues to identify cell types and their likely functions, including whether they secrete growth, angiogenic, or suppressive proteins. In this project, we will leverage these advances in mouse models to generate a clearer understanding of whether immature myeloid cells support melanoma establishment directly through the provision of growth signals and/or indirectly through the initiation of an immune-suppressive environment. At the end of this project, we will have developed a new understanding of mechanisms that (1) support the establishment and growth of melanoma and (2) shield melanomas from immune attack as they form. These findings will support new avenues of research that can be explored, for example, to block the provision of growth signals and prevent the formation of melanoma in the first place, or to switch on the immune system at very early stages of disease to stop the growth of emerging tumors. In the past decade there has been immense progress in our ability to harness the immune system to treat cancer – indeed, cancer immunotherapy was named Breakthrough of the Year 2013 by the top-level journal Science. Immunotherapy is taking its place as a go-to therapy for late-stage melanoma, which is remarkable when the levels of immune dysfunction and dysregulation present at these late stages are taken into account. However, treating melanoma at late stages requires systemic treatment strategies, which due to their non-specific nature cause a host of unpleasant and unwanted side effects such as diarrhea, pneumonitis, vomiting, and fatigue. Unfortunately, these side effects can become so severe that patients elect to stop their treatment. The knowledge generated in this project is targeted toward the treatment of disease at earlier stages, when tumor burden is local
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210902
Entities
People
- James A. Wells
Organizations
- United States Army
- University of Queensland