Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration.
Yifan ZhouYusra B MedikBhakti PatelDaniel B ZamlerSijie ChenThomas ChapmanSarah M SchneiderElizabeth M ParkRachel L BabcockTaylor T ChrisikosLaura M KahnAllison M DyevoichJosué E PinedaMatthew C WongAditya K MishraSamuel H CassAlexandria P CogdillDaniel H JohnsonSarah B JohnsonKhalida M WaniDebora A LedesmaCourtney W HudgensJingjing WangMd Abdul Wadud KhanChristine B PetersonAron Y JoonWeiyi PengHaiyan S LiReetakshi AroraXiming TangMaria Gabriela RasoXuegong ZhangWai Chin FooMichael T TetzlaffGretchen E DiehlKaren Clise-DwyerElizabeth M WhitleyMatthew M GubinJames P AllisonPatrick HwuNadim J AjamiAdi DiabJennifer A WargoStephanie S WatowichPublished in: The Journal of experimental medicine (2022)
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 systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.
Keyphrases
- oxidative stress
- high fat diet induced
- ulcerative colitis
- genome wide
- metabolic syndrome
- liver failure
- stem cells
- dendritic cells
- dna methylation
- insulin resistance
- gene expression
- skeletal muscle
- type diabetes
- adipose tissue
- hepatitis b virus
- combination therapy
- extracorporeal membrane oxygenation
- ultrasound guided