{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:17:18Z","timestamp":1792804638819,"version":"4.5.0"},"reference-count":114,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T00:00:00Z","timestamp":1666915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Skin melanoma cells are tightly interconnected with their tumor microenvironment (TME), which influences their initiation, progression, and sensitivity\/resistance to therapeutic interventions. An immune-active TME favors patient response to immune checkpoint inhibition (ICI), but not all patients respond to therapy. Here, we assessed differential gene expression in primary and metastatic tumors from the TCGA-SKCM dataset, compared to normal skin samples from the GTEx project and validated key findings across 4 independent GEO datasets, as well as using immunohistochemistry in independent patient cohorts. We focused our attention on examining the expression of various immune receptors, immune-cell fractions, immune-related signatures and mutational signatures across cutaneous melanomas with diverse tumor mutation burdens (TMB). Globally, the expression of most immunoreceptors correlated with patient survival, but did not differ between TMB\n                    <jats:sup>high<\/jats:sup>\n                    and TMB\n                    <jats:sup>low<\/jats:sup>\n                    tumors. Melanomas were enriched in\n                    <jats:italic>\u201cnaive T-cell\u201d, \u201ceffector memory T-cell\u201d, \u201cexhausted T-cell\u201d, \u201cresting Treg T-cell\u201d<\/jats:italic>\n                    and\n                    <jats:italic>\u201cTh1-like\u201d<\/jats:italic>\n                    signatures, irrespective of their\n                    <jats:italic>BRAF<\/jats:italic>\n                    ,\n                    <jats:italic>NF1<\/jats:italic>\n                    or\n                    <jats:italic>RAS<\/jats:italic>\n                    mutational status. Somatic mutations in\n                    <jats:italic>IDO1<\/jats:italic>\n                    and\n                    <jats:italic>HLA-DRA<\/jats:italic>\n                    were frequent and could be involved in hindering patient response to ICI therapies. We finally analyzed transcriptome profiles of ICI-treated patients and associated their response with high levels of IFN\u03b3, Merck18, CD274, CD8, and low levels of myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs) and M2 macrophages, irrespective of their TMB status. Overall, our findings highlight the importance of pre-existing T-cell immunity in ICI therapeutic outcomes in skin melanoma and suggest that TMB\n                    <jats:sup>low<\/jats:sup>\n                    patients could also benefit from such therapies.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.1006665","type":"journal-article","created":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T07:25:02Z","timestamp":1666941902000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden"],"prefix":"10.3389","volume":"13","author":[{"given":"George","family":"Georgoulias","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apostolos","family":"Zaravinos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/35020115","article-title":"Molecular classification of cutaneous malignant melanoma by gene expression profiling","volume":"406","author":"Bittner","year":"2000","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1007\/978-0-387-77574-6_8","article-title":"Epidemiology of melanoma and nonmelanoma skin cancer\u2013the role of sunlight","volume":"624","author":"Leiter","year":"2008","journal-title":"Adv Exp Med 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