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Manipulation of co-inhibitory receptors has achieved tumor eradication in a minority of patients, but widespread immune-related adverse events (irAEs) compromised tolerance to healthy self-tissues in the majority. We have proposed that a major mechanism of irAEs is similar to a graft-versus-malignancy effect of graft-versus-host disease. To verify our hypothesis, we retrieved post-marketing data of adverse events from the U.S. Food and Drug Administration Adverse Event Reporting System. A significant positive correlation was revealed in 7677 patients between the reporting odds ratio of irAEs during immune checkpoint inhibitor therapy and the corresponding tumor mutational burden across 19 cancer types. These results can be interpreted to mean that the ICI drugs unleashed T cells against \u201caltered-self,\u201d self, and tumors resulting in better overall survival.<\/jats:p>","DOI":"10.1007\/s00262-020-02543-6","type":"journal-article","created":{"date-parts":[[2020,3,9]],"date-time":"2020-03-09T13:02:39Z","timestamp":1583758959000},"page":"683-687","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Significant association between tumor mutational burden and immune-related adverse events during immune checkpoint inhibition therapies"],"prefix":"10.1007","volume":"69","author":[{"given":"Csaba","family":"Kerepesi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tibor","family":"Bakacs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralph W.","family":"Moss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shimon","family":"Slavin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1733-4237","authenticated-orcid":false,"given":"Colin C.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,3,9]]},"reference":[{"key":"2543_CR1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.3221","author":"D Bomze","year":"2019","unstructured":"Bomze D, Hasan Ali O, Bate A, Flatz L (2019) Association between immune-related adverse events during anti-PD-1 therapy and tumor mutational burden. 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All other authors have none to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This study was exempt from ethical review because all analyzed datasets are deidentified and publicly available.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and ethical standards"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}