{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T16:22:55Z","timestamp":1780330975797,"version":"3.54.1"},"reference-count":23,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"unspecified","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA227472"],"award-info":[{"award-number":["R01 CA227472"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,8,27]]},"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:p>Immune checkpoint inhibitors (ICIs) have improved survival of patients with cancer, yet they pose risks of immune-related adverse events (irAEs). ICI-induced insulin-dependent diabetes mellitus (ICI-DM) is a life-threatening and life-altering irAE. Previously, we reported a high incidence of a germline missense variant in <jats:italic>NLRC5<\/jats:italic>, a key class I transcription activator, among patients with ICI-DM compared with similarly treated patients who did not develop ICI-DM. Our purpose was to validate this finding in additional ICI-treated patients and study effects of the <jats:italic>NLRC5<\/jats:italic> variant on expression of class I major histocompatibility complex (MHC) antigen presentation genes.<\/jats:p>\n               <jats:p>We assessed the prevalence of the C&gt;T missense variant at chr16:57\u2009025\u2009515 (<jats:italic>NLRC5Pro191Leu<\/jats:italic>) in germline DNA from an additional 33 patients with ICI-DM and in patients with ICI-induced colitis (n=15), ICI-induced hypothyroidism (n=19) and ICI-induced hypophysitis (n=17). The 1,000 Genomes Project was used for comparison. We assessed peripheral blood mononuclear cells from 16 individuals with or without the <jats:italic>NLRC5<\/jats:italic> variant, studying expression of <jats:italic>NLRC5<\/jats:italic> and select downstream target genes, before and after stimulation with interferon-\u03b3.<\/jats:p>\n               <jats:p>We validated the higher prevalence of <jats:italic>NLRC5Pro191Leu<\/jats:italic> in a non-overlapping cohort of patients with ICI-DM compared with the general population (51.5% vs 12.8%, p&lt;0.0001). The prevalence of <jats:italic>NLRC5Pro191Leu<\/jats:italic> in ICI-induced colitis or thyroiditis patients did not significantly differ from the general population, while the prevalence in ICI-induced hypophysitis was somewhat higher (21.6%, p=0.048). We found greater increases in messenger RNA expression of <jats:italic>NLRC5<\/jats:italic> (p=0.007), <jats:italic>TAP1<\/jats:italic> (p=0.0002), <jats:italic>B2M<\/jats:italic> (p=0.0005), <jats:italic>HLA-G<\/jats:italic> (p=0.04), <jats:italic>PSMB8<\/jats:italic> (p=0.03) and <jats:italic>PSMB9<\/jats:italic> (p=0.01) in <jats:italic>NLRC5Pro191Leu<\/jats:italic> cells stimulated with interferon-\u03b3 compared with <jats:italic>NLRC5<jats:sup>WT<\/jats:sup>\n                  <\/jats:italic> cells. A similar trend was observed for <jats:italic>HLA-A<\/jats:italic> (p=0.09).<\/jats:p>\n               <jats:p>We confirm the significantly higher prevalence of the <jats:italic>NLRC5Pro191Leu<\/jats:italic> variant in patients with ICI-DM relative to the general population. This abundance appears to be unique to patients who develop ICI-DM or hypophysitis on ICIs, underscoring its potential involvement in the pathogenesis of these endocrinopathies. The effects of this <jats:italic>NLRC5<\/jats:italic> variant on class I MHC regulators suggest a mechanistic connection between the variant and development of ICI-DM. Further work is warranted to determine whether class I MHC molecules can be modulated in patients with the <jats:italic>NLRC5Pro191Leu<\/jats:italic> variant requiring ICIs.<\/jats:p>","DOI":"10.1136\/jitc-2025-012358","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T06:35:13Z","timestamp":1757572513000},"page":"e012358","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Factors that increase class I MHC expression may contribute to the development of immune checkpoint inhibitor-induced diabetes"],"prefix":"10.1136","volume":"13","author":[{"given":"Lilach","family":"Aizenbud","sequence":"first","affiliation":[{"name":"Medical Oncology, Yale University, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5638-1151","authenticated-orcid":false,"given":"Noam","family":"Savion Gaiger","sequence":"additional","affiliation":[{"name":"Medical Oncology, Yale University, New Haven, Connecticut, USA"},{"name":"Smilow Cancer Hospital at Yale New Haven, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Luisa","family":"Perdigoto","sequence":"additional","affiliation":[{"name":"Endocrinology and Metabolism, Yale University, New Haven, Connecticut, USA"},{"name":"Internal medicine, VA Connecticut Healthcare System, West Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline E","family":"Mann","sequence":"additional","affiliation":[{"name":"Medical Oncology, Yale University, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline Candelas","family":"Torres","sequence":"additional","affiliation":[{"name":"Endocrinology and Metabolism, Yale University, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve M","family":"Boland","sequence":"additional","affiliation":[{"name":"Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleigha R","family":"Lawless","sequence":"additional","affiliation":[{"name":"Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahar","family":"Silverman","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5202-3744","authenticated-orcid":false,"given":"David Aaron","family":"Schoenfeld","sequence":"additional","affiliation":[{"name":"Medical Oncology, Yale University, New Haven, Connecticut, USA"},{"name":"Smilow Cancer Hospital at Yale New Haven, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jodhel I","family":"Destina","sequence":"additional","affiliation":[{"name":"Yale University, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitzan","family":"Hasson","sequence":"additional","affiliation":[{"name":"Medical Oncology, Yale University, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6244-7575","authenticated-orcid":false,"given":"Thuy","family":"Tran","sequence":"additional","affiliation":[{"name":"Medical Oncology, Yale University, New Haven, Connecticut, USA"},{"name":"Smilow Cancer Hospital at Yale New Haven, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hurwitz","sequence":"additional","affiliation":[{"name":"Medical Oncology, Yale University, New Haven, Connecticut, USA"},{"name":"Smilow Cancer Hospital at Yale New Haven, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R","family":"Austin","sequence":"additional","affiliation":[{"name":"Medical Oncology, Yale University, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5344-6645","authenticated-orcid":false,"given":"Ryan J","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevan C","family":"Herold","sequence":"additional","affiliation":[{"name":"Endocrinology and Metabolism, Yale University, New Haven, Connecticut, USA"},{"name":"Immunology, Yale University, New Haven, Connecticut, 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