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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

Abstract The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA sequencing and T cell receptor (TCR) sequencing to detect and characterize “tumor matching” (TM) CD8+ T cells in the blood of mice with MC38 tumors and melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared to non-matching T cells in blood, and appeared less exhausted than matching counterparts in tumor. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome we identified candidate cell surface marker panels for TM cells in mice and melanoma patients, and validated NKG2D, CD39, and CX3CR1 in mice. These data demonstrate that the TCR can be used to identify tumor-relevant populations for comprehensive characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells. Summary Using single-cell RNA-sequencing coupled with TCR sequencing, we detected CD8+ T cell clones shared between blood and tumor in mice and melanoma patients, characterized these matching clones in blood and tumor, and identified potential biomarkers for their isolation in blood. Competing Interest Statement The authors declare the enclosed potential conflicts of interest. M.D.R. is a founder of TRex Bio and Sitryx Bio and receives research funding from Abbvie, LEO Pharma, and TRex bio. A.I.D. has funds from Merck, Oncosec, BMS, Roche, Genentech, Pfizer, Incyte, Novartis and Checkmate, is on advisory boards for Xencor, Pfizer, Array, has stock in TRex, SQZ bio., and patents with Oncosec on Gene Therapy of melanoma. A.H.S. has patents on the PD-1 pathway licensed by Roche/Genentech and Novartis, consults for Novartis, is on the scientific advisory boards for Surface Oncology, Sqz Biotech, Elstar Therapeutics, Elpiscience, Selecta and Monopteros, and has research funding from Merck, Novartis, Roche, and Quark Ventures. K.K.T discloses institutional research funding from Array/Pfizer, BMS, Oncosec, Regeneron, and Replimune. From August 4th 2020, MS is an employee of Guardant Health. The authors have no additional financial conflicts of interest to disclose. Footnotes * ↵+ co-first authors