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Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research.<\/jats:p>","DOI":"10.1038\/s41467-021-25860-5","type":"journal-article","created":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T13:24:52Z","timestamp":1634045092000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Genomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases"],"prefix":"10.1038","volume":"12","author":[{"given":"Sanjay M.","family":"Prakadan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Alvarez-Breckenridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel 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P.K.B. has received compensation for consulting from Lilly, Angiochem, ElevateBio, Voyager Therapeutics,\u00a0Tesaro and Genentech-Roche, SK Life Sciences, Pfizer and Dantari and Speaker\u2019s Honoraria from Genentech-Roche and Merck Sharp & Co. PKB has received research funding (to MGH) from Merck & Co, BMS, Eli Lilly, Mirati\u00a0and Pfizer. D.P.C. has received compensation for consulting from Eli Lilly & Co. and received honoraria from Merck & Co. DR has consulting and compensation interests in Celsius Therapeutics. S.M.P., C.A.A., S.C.M., S.L.C., P.K.B., and A.K.S. are co-inventors on a provisional patent application filed by the Broad Institute relating to the techniques and findings described in this manuscript. The other authors have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5955"}}