biostudies-literatureZhou YParker Institute for Cancer ImmunotherapyNIAID NIH HHSNational Heart, Lung, and Blood InstituteNHLBI NIH HHSNational Cancer InstituteNCI NIH HHSNational Institutes of HealthUniversity of Texas MD AndersonWilks Family FundCancer Prevention and Research Institute of Texase20221333https://www.ebi.ac.uk/biostudies/studies/S-EPMC9664499biostudies-literatureUnknown220(2)Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)-mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4-mediated irAEs, including colonic neutrophil accumulation and sThe Journal of experimental medicineIntestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration.PMC9664499R01 AI133822P50 CA221703P30CA016672R01AI109294CA016672P30CA0166722R01 HL158796P30 CA008748RP170067T32 CA009599RP2100283R01CA187076-05S1CA009599R01AI109294-04S1P30 CA016672HL158796R01AI133822RR190017P50CA221703R01 AI109294R01 CA187076Kahn LMWong MCMishra AKPeng WFoo WCPeterson CBPatel BWhitley EMGubin MMCass SHWang JPark EMWargo JAWani KJoon AYArora RCogdill APJohnson SBLedesma DADiehl GEDiab AZamler DBChen SPineda JETang XWadud Khan MAAllison JPWatowich SSRaso MGSchneider SBabcock RLDyevoich AMJohnson DHChrisikos TTZhou YClise-Dwyer KLi HSTetzlaff MTMedik YBChapman TZhang XHudgens CWHwu PAjami NJfalseIntestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration.Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)-mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4-mediated irAEs, including colonic neutrophil accumulation and s2023-01-01T00:00:00Z2023 Feb2025-04-22T07:47:30.37Z2025-04-05T22:15:53.069ZS-EPMC96644993636777610.1084/jem.20221333