Melanoma-derived brain metastases (MBM) represent an unmet clinical need due to central nervous system (CNS) progression as a frequent, end-stage site of disease. Immune checkpoint inhibition (ICI) represents a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique MBM-TME elements and correlates of MBM-ICI response, we collected 32 fresh MBM and performed single cell RNA sequencing of the MBM-TME and T cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity, most notably multiple distinct neutrophil states including an IL-8 expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. Additionally, we observe significant relationships between intracranial T cell phenotypes and the distribution of T cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data demonstrate unique features of the MBM-TME, which may represent potential targets to improve clinical outcomes for patients with MBM. Competing Interest Statement PKB has received compensation for consulting from Lilly, Angiochem, ElevateBio, Tesaro and Genentech-Roche, SK Life Sciences, Pfizer and Dantari and Speaker's Honoraria from Genentech-Roche and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD). PKB has received research funding (to MGH) from MSD, BMS, Eli Lilly and Pfizer. MLS is equity holder, scientific co-founder and advisory board member of Immunitas Therapeutics. BCM consults for Cellarity, Inc. in immuno-oncology. MAD has been a consultant to Roche/Genentech, Array, Pfizer, Novartis, BMS, GSK, Sanofi-Aventis, Vaccinex, Apexigen, Eisai, and ABM Therapeutics, and he has been the PI of research grants to MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. The other authors have no competing interests. Footnotes * https://singlecell.broadinstitute.org/single_cell/study/SCP1493/microenvironmental-correlates-of-immune-checkpoint-inhibitor-response-in-human-melanoma-brain-metastases-revealed-by-t-cell-receptor-and-single-cell-rna-sequencing...

Microenvironmental correlates of immune checkpoint inhibitor response in human melanoma brain metastases revealed by T cell receptor and single-cell RNA sequencing

10.1101/2021.08.25.456956