Abstract 3851: Vascular regulation of immune exclusion in melanoma

Abstract The infiltration of immune cells into the tumor is as crucial as their activity in determining the responses to immune checkpoint inhibitors (ICIs). Immune cell exclusion from tumors has been linked to poor responses to ICIs across various cancers, including melanoma; however, the underlying biological mechanisms remain poorly understood. Abnormal tumor vasculature, characterized by leakage and instability, represents a key barrier to immune cell infiltration, but the mechanisms underpinning these vascular changes and their impact on immune exclusion development remain poorly understood.To address this, we utilized a syngeneic mouse melanoma model to investigate the role of vascular changes in regulating immune cell positioning and exclusion during tumor progression. Spatial distribution of various immune cell populations and vascular integrity were assessed through multiplexed immunofluorescence staining across whole tumor cross-sections. While early-stage tumors exhibit well-infiltrated CD8+ T cells and neutrophils throughout the tumors, these immune cells became confined to the tumor periphery as tumors grew, leaving the core devoid of infiltration. This immune exclusion development correlated with vascular instability and leakage, particularly observed at the tumor periphery. Transcriptomic analysis of endothelial cells, sorted from the tumor periphery and core revealed increased gene expression of chemotaxis and immune migration in endothelial cells at the tumor periphery. Through multi-omics approaches including single-cell and spatial transcriptomic analysis, we aim to unravel the molecular mechanisms by which vascular abnormalities shape immune cell exclusion. These findings will guide us in building strategies to restore vascular integrity, enhance immune cell infiltration, and improve the efficacy of ICIs, addressing critical unmet needs for melanoma patients resistant to current immunotherapies. Citation Format: Ha-Ram Park, Nika Kozolv, Shawn Jaeha Kim, Eugene Son, Sungsoo Kim, Hee Won Yang, Minah Kim. Vascular regulation of immune exclusion in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3851.