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The relationship of irAEs with baseline parameters and clinical outcome is unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Retrospective evaluation of irAEs on survival was performed across primary (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u2009144) and secondary (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u2009211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab\/nivolumab\u2014sICB) or combination (nivolumab and ipilimumab\u2014cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells was sequenced and differential gene expression according to irAE development assessed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS:\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9\u201333.4) versus not-reached (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20092.8\u2009\u00d7\u200910\n                      <jats:sup>\u22126<\/jats:sup>\n                      ). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells according to irAE development, and patients not developing irAEs demonstrating upregulated\n                      <jats:italic>CXCR1<\/jats:italic>\n                      pre- and post-treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s41416-021-01310-3","type":"journal-article","created":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T06:03:28Z","timestamp":1615788208000},"page":"1661-1669","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles"],"prefix":"10.1038","volume":"124","author":[{"given":"Weiyu","family":"Ye","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7721-5817","authenticated-orcid":false,"given":"Anna","family":"Olsson-Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Watson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent T. 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Samples from the Clatterbridge Cancer Centre approval was approved for the HYST study: 12\/NW\/0525, local approval 17\u201318\/40.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Sequencing data deposited at European Genome\u2013phenome Archive under accession no.\n                      \n                      , available via a data access agreement.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"M.R.M. reports personal fees from Amgen, grants and personal fees from Roche, grants from Astrazeneca, grants and personal fees from GSK, personal fees and other from Novartis, other from Millenium, personal fees, non-financial support and other from Immunocore, personal fees and other from BMS, personal fees and other from Eisai, other from Pfizer, personal fees, non-financial support and other from Merck\/MSD, personal fees and other from Rigontec (acquired by MSD), other from Regeneron, personal fees from BiolineRx, personal fees and other from Array Biopharma (now Pfizer), non-financial support and other from Replimune, outside the submitted work. M.P. has received support with conference travel, and fees for advisory work and speaking from Amgen, BMS, L\u2019Oreal, MSD, Novartis and Pierre Fabre. BPF received support with conference travel from BMS. All other authors report no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This work was supported by National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. B.P.F. is Wellcome funded (201488\/Z\/16\/Z). A.C.O.B. is MRC funded (MR\/N025989\/1).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding information"}}]}}