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k/vol1/fastq/SRR128/042/SRR12880542/SRR12880542_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR128/078/SRR12880478/SRR12880478_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR128/036/SRR12880536/SRR12880536_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR128/030/SRR12880530/SRR12880530_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR128/045/SRR12880545/SRR12880545_2.fastq.gzprimaryOK200GenomicsMD Anderson Cancer Centerhttps://www.ebi.ac.uk/ena/browser/view/PRJNA670730Immunotherapies such as immune checkpoint blockade (ICB) have revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by development of off-target tissue toxicities, collectively termed immune-related adverse events (irAEs). At present, there is limited understanding of irAE-driving mechanisms based in part on a paucity of irAE animal models. We reasoned that disruption of homeostatic immunity is important to sensitize otherwise healthy mice to ICB-associated irAEs. Our studies in inflammation-prone and acute infectious colitis models revealed anti-CTLA-4-mediated intestinal toxicity. Neutrophils, interferon-gamma-producing, and cytotoxic T cells were recruited to the gut, accompanied by increased production of pro-inflammatory cytokines, and an aberrant microbiome. Importantly, neutrophil, T helper 1 (Th1), and cytotoxic signatures were validated in samples from patients who developed colitis during treatment with ICB, supporting the utility of our approach. In inflammation-prone mice, treatment with anti-CTLA-4 was associated with increased myelopoiesis and blunted tumor control compared to wild-type controls, while depletion of neutrophils or interleukin-6 (IL-6) blockade enhanced anti-CTLA-4 therapeutic efficacy and reduced irAE-associated immune signatures. Together, these data suggest anti-CTLA-4 promotes myeloid infiltration and intestinal irAEs in inflammation-prone conditions. This work provides mechanistic insight into irAE development and models for pre-clinical investigation, with potential therapeutic implications to decrease irAEs and enhance anti-tumor immunity.ENAfalseIntestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration2023-05-172022-11-09PRJNA670730