Unraveling the Evolution of Melanoma Within the Host Immune Ecosystem
Abstract
Our research proposal, Unraveling the evolution of melanoma within the host immune ecosystem, seeks to understand how the tumor-immune microenvironment impacts melanoma initiation and progression. This research question is one of the fiscal year 2022 Melanoma Research Program Focus Areas due to its implications for prevention throughout the disease progress. It is widely accepted that melanoma is the result of the gradual accumulation of mutations that increase cell proliferation. Additionally, melanomas often arise from distinct precursor lesions, which makes the analysis of their initiation and progression possible. Thousands of melanomas have been sequenced to date and their analysis has revealed high burden of somatic mutation with clear patterns implicating sunlight as a major mutagen driving their development. Furthermore, the succession of major genetic alterations that accumulate during melanoma evolution has been demonstrated. However, how the immune microenvironment impacts tumor initiation and progression remains poorly understood. Better understanding of how the local immune microenvironment shapes the genetic evolution of melanoma would have implications for the development of biomarkers for early detection of melanoma as well as the development of novel targets for therapeutic intervention. The major clinical unmet challenge we face in the field of melanoma is that we have identified many genetic alterations in these tumors and demonstrated their sequential order accumulating during melanoma initiation and progression, but we do not yet have the necessary biological knowledge of how the immune microenvironment is affecting their evolution, how to use this knowledge for early detection of melanoma, and how to target these tumors with effective therapies. To tackle this significant challenge, we have formed a multidisciplinary multi-institutional team. Our team brings together scientific experts in molecular melanoma genetics and molecular pathology as well as computational immunology and cancer immunotherapy; and new machine learning-based analyses of large cancer genetics datasets; and clinical oncology experts in melanoma. In Aim 1, we will analyze patients with melanomas with their adjacent precursor lesions and normal tissues to identify cell-intrinsic and -extrinsic alterations that promote immune escape during melanoma progression. This analysis will allow us to assess whether escape from immunosurveillance such as neoantigen immunoediting represents a critical requirement for a melanoma to become metastatic. In Aim 2, we will study the stage-specific genetic alterations with the changes in the immune microenvironment to formulate a model of the co-evolution of tumor cells and the immune microenvironment during melanoma development. This analysis will allow us to model possible cause and effect relationships between genetic changes in the tumor cells and changes in the immune microenvironment. This knowledge will be important to improve our understanding of melanoma evolution. In Aim 3, we will study the localization and spatial relationships among the different immune cell subsets by applying cutting-edge spatial profiling techniques. For the first time, we will analyze matched primary melanoma lesions and precancerous lesions using spatial-resolution technologies with the focus to characterize dynamic composition of the tumor-immune microenvironment and its relationship to tumor-immune control and escape. With these three aims, we will learn important information about what genetic alterations in melanoma mean for the immune microenvironment. By understanding the role of the immune microenvironment, we will be able to develop effective classifiers to detect melanoma in the early evolutionary process and develop new therapies. This study s analyses and experiments will allow us to find new markers of the behavior of the tumor-immune microenvironment—to help clinicians det
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310870
Entities
People
- Diego Chowell
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army