{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:08:34Z","timestamp":1790352514750,"version":"4.1.0"},"reference-count":49,"publisher":"American Society for Clinical Investigation","issue":"11","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":60,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007299","name":"Harvard Catalyst","doi-asserted-by":"crossref","award":["KL2TR002542"],"award-info":[{"award-number":["KL2TR002542"]}],"id":[{"id":"10.13039\/100007299","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100005984","name":"Dr. Miriam and Sheldon G. Adelson Medical Research Foundation","doi-asserted-by":"crossref","award":["04-7023433"],"award-info":[{"award-number":["04-7023433"]}],"id":[{"id":"10.13039\/100005984","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100011495","name":"Massachusetts Life Sciences Center","doi-asserted-by":"crossref","award":["Mass General Cancer Center Tumor Cartography Center"],"award-info":[{"award-number":["Mass General Cancer Center Tumor Cartography Center"]}],"id":[{"id":"10.13039\/100011495","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,8]]},"abstract":"<jats:p>\n                    Recent innovations in melanoma treatment with immune checkpoint blockade (ICB) have improved overall outcomes for patients; however, over 50% of patients still develop resistance to treatment. These patients either have intrinsic resistance and never respond to therapy or develop acquired resistance months or years into treatment. The mechanisms underlying ICB resistance remain poorly understood. Our data show that patients with isocitrate dehydrogenase gain-of-function (\n                    <jats:italic>IDH<\/jats:italic>\n                    GOF) mutant melanoma have a worse response to anti-PD1 immunotherapy.\n                    <jats:italic>IDH<\/jats:italic>\n                    mutations have been found to be oncogenic and associated with differential methylation in multiple cancers but are not yet characterized in human melanoma. Here, we investigate the clinical, immune, and transcriptional phenotypes of\n                    <jats:italic>IDH<\/jats:italic>\n                    GOF melanomas through analyses of clinical response, single-cell RNA-seq, bulk RNA-seq, and DNA methylation data. Single-cell data analysis showed decreased immune infiltrate and activity in the\n                    <jats:italic>IDH<\/jats:italic>\n                    GOF tumors. Bulk sequencing data demonstrated the association among\n                    <jats:italic>IDH<\/jats:italic>\n                    mutation, immune exclusion, and disruptions in global DNA methylation. The melanoma-derived genomic data presented support previously described resistance mechanisms of\n                    <jats:italic>IDH<\/jats:italic>\n                    mutation in other cancer types and is the first demonstration to our knowledge of the role of\n                    <jats:italic>IDH<\/jats:italic>\n                    GOF in the human melanoma tumor microenvironment.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.195384","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T16:00:22Z","timestamp":1775750422000},"source":"Crossref","is-referenced-by-count":1,"title":["Loss of tumor-infiltrating lymphocytes and poor response to immunotherapy in IDH GOF mutant melanoma"],"prefix":"10.1172","volume":"11","author":[{"given":"Emma","family":"Specht","sequence":"first","affiliation":[{"name":"Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lakshmi","family":"Pakanati","sequence":"additional","affiliation":[{"name":"Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Ju","family":"Wu","sequence":"additional","affiliation":[{"name":"Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."},{"name":"Division of Gastroenterology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell W.","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."},{"name":"Division of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek N.","family":"Effiom","sequence":"additional","affiliation":[{"name":"Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabeel","family":"Bardeesy","sequence":"additional","affiliation":[{"name":"Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley E.","family":"Bernstein","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Departments of Cell Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moshe","family":"Sade-Feldman","sequence":"additional","affiliation":[{"name":"Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine G.","family":"Lian","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve M.","family":"Boland","sequence":"additional","affiliation":[{"name":"Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Torlai Triglia","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA."},{"name":"School of Biological and Behavioural Sciences, Queen Mary University of London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2014.11.008"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910836"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.24.01124"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2019-000398"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31345"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.044"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-021-00521-0"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15112883"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27150-6"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2024.114190"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2021.04.005"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1176994"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-0292-x"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01331-8"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12071791"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2015.412"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1126\/science.adl6173"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.103877"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1101\/gad.2037511"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1077"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1995.13.4.910"},{"issue":"6","key":"B23","first-page":"488","article-title":"Treatment of metastatic melanoma: an overview","volume":"23","author":"Bhatia","year":"2009","journal-title":"Oncology (Williston Park)"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"B25","unstructured":"R: A Language and Environment for Statistical Computing. The R Project for Statistical Computing. https:\/\/www.R-project.org"},{"key":"B26"},{"key":"B27","unstructured":"survminer: Drawing Survival Curves using \u201cggplot2.\u201d Version 0.5.2. The CRAN R project; 2026. https:\/\/CRAN.R-project.org\/package=survminer"},{"key":"B28","unstructured":"ggplot2: Elegant Graphics for Data Analysis. Version 4.0.0. Springer-Verlag New York; 2016. https:\/\/ggplot2.tidyverse.org"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1507"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-020-0077-8"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.xinn.2021.100141"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1126\/science.ade2292"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3791\/66766"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-023-01943-7"},{"key":"B36"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0"},{"key":"B38","unstructured":"McKinney W. Data Structures for Statistical Computing in Python. Presented at: The 9th Python in Science Conference; June 28\u2013July 3, 2010; Austin, Texas, USA. https:\/\/proceedings.scipy.org\/articles\/Majora-92bf1922-00a Accessed April 8, 2026"},{"key":"B39","doi-asserted-by":"crossref","unstructured":"Clarke ZA, Bader GD. MALAT1expression indicates cell quality in single-cell RNA sequencing data [preprint]. https:\/\/doi.org\/10.1101\/2024.07.14.603469 Posted on bioRxiv July 17, 2024","DOI":"10.1101\/2024.07.14.603469"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-024-11015-5"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2018.11.005"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-0922-4"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.10.038"},{"key":"B44","unstructured":"infercnvpy: Infer copy number variation (CNV) from scRNA-seq data. Plays nicely with Scanpy. Version 0.6.1. Github; 2025. https:\/\/github.com\/icbi-lab\/infercnvpy"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04682-5"},{"key":"B46","unstructured":"Seaborn: Statistical data visualization.Version 0.13.2. Seaborn; 2021. https:\/\/seaborn.pydata.org"},{"key":"B47","unstructured":"Matplotlib \u2014 visualization with python. https:\/\/matplotlib.org\/"},{"key":"B48","unstructured":"harmonypy: Integrate multiple high-dimensional datasets with fuzzy k-means and locally linear adjustments. Version 0.2.0. Github 2026. https:\/\/github.com\/slowkow\/harmonypy"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw313"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/195384\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T18:26:12Z","timestamp":1782757572000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/195384"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,9]]},"references-count":49,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,4,23]]},"published-print":{"date-parts":[[2026,6,8]]}},"alternative-id":["10.1172\/jci.insight.195384"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.195384","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,9]]},"article-number":"e195384"}}