Brain-Metastatic Melanoma Models Uncover Immune and Molecular Correlates of Response to Immunotherapy

Abstract

SUMMARYDespite promising results with immune checkpoint blockade (ICB) therapy, outcomes of patients with brain metastasis (BrM) remain poor. Identifying determinant of resistance is crucial but has been hindered by limited access to patient samples and the scarcity of relevant preclinical models. Here, we developed two mouse melanoma BrM models that mirror the disparate response to ICB seen in patients. By characterizing their mutational landscape and performing single-cell phenotypic and transcriptomic analysis, we demonstrated that these models recapitulate both the cellular and molecular features of human disease. Through our comparative analysis, we identified key factors contributing to ICB response. In the responsive model, we found that tumor cells expressed inflammatory programs that polarized microglia toward reactive states, expressing high levels of MHC-I and -II and immunostimulatory molecules, eliciting robust T cell recruitment and activation, which favored anti-tumor immunity. Conversely, the resistant melanoma cells were characterized by neurological molecular signatures and expression of ligands that maintain microglia homeostatic states, resulting in poor T cell infiltration and therapy resistance. We validated our findings in BrM patients, showing that BR1 and BR3 signatures correlated with T cell infiltration and were associated with better and worse patient outcomes, respectively. Our study fills a critical gap by providing clinically relevant models and revealing mechanistic insights into BrM ICB responses, identifying potential biomarkers and therapeutic targets.