Spatial Vascular Patterns and Immune Exclusion Mechanisms in Melanoma

Melanoma is the most aggressive type of skin cancer and is responsible for the majority of skin cancer deaths. While new treatments have benefited many melanoma patients, a significant number either do not respond or show disease progression after an initial response. This underscores the need to understand how tumors promote immune suppression, which can lead to resistance to immunotherapies. Effective treatment response requires not only cancer-specific T cells but also physical contact between T cells and tumor cells. However, the biology that underpins this immune exclusion pattern remains unclear. Our recent study demonstrated that abnormal tumor blood vessels promote the exclusion of T cells from the tumor core in melanoma. Specifically, we found that angiopoietin-2 (ANGPT2), a vascular destabilizing factor, induces spatial vascular leakage at the tumor periphery and contributes to T-cell exclusion from the tumor core. Building on this, in the proposed study, we will employ multi-omics methodologies and investigate vascular determinants of the development of immune exclusion (Aim 1) and elucidate the molecular mechanisms of ANGPT2-driven T-cell exclusion in melanoma (Aim 2). Our work could identify novel vascular targets, pathways, and mechanisms that govern the development and progression of immune exclusion to enhance the current immunotherapies for melanoma. Furthermore, our insights will lay the groundwork for a clinical study evaluating the effects of T-cell exclusion on the efficacy of immunotherapy in melanoma patients.