{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T21:17:43Z","timestamp":1783372663148,"version":"3.54.6"},"posted":{"date-parts":[[2026,7,3]]},"group-title":"Immunology","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Over one million patients receive cancer immunotherapy annually, yet the mechanisms underlying life-threatening immune-mediated toxicities remain poorly understood. Checkpoint inhibitor pneumonitis (CIP) is the leading cause of immunotherapy-related mortality, with a case fatality rate approaching 10%, and no genetic risk factors have been described to date. We identified Dipeptidyl-peptidase 9 (DPP9) as the first genetic susceptibility gene for CIP in a clinico-genomics cohort of 4,397 patients treated with immune checkpoint inhibitors. Mechanistically, DPP9 suppresses CARD8 inflammasome activation and IL-18 secretion in human monocytes, a pathway which is engaged prior to CIP onset, with IL-18 selectively elevated in the plasma of patients who subsequently develop CIP. Myeloid-restricted ablation of\n                  <jats:italic>Dpp8<\/jats:italic>\n                  and\n                  <jats:italic>Dpp9<\/jats:italic>\n                  in mice recapitulated the pulmonary histopathological and immunological hallmarks of CIP, including granuloma formation, accumulation of IFN\u03b3-producing T cells and monocyte-derived macrophages. Each of these phenotypes were driven by excessive IL-18 secretion. Together, these findings establish DPP9 as a genetic determinant of CIP and nominate IL-18 blockade as a mechanistically rational therapeutic strategy.\n                <\/jats:p>","DOI":"10.64898\/2026.06.30.735609","type":"posted-content","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T09:56:42Z","timestamp":1783072602000},"source":"Crossref","is-referenced-by-count":0,"title":["DPP9-mediated inflammasome repression protects against checkpoint inhibitor lung toxicity"],"prefix":"10.64898","author":[{"given":"J. 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