To address mechanisms underlying immune-related adverse events (irAEs) commonly seen with immune checkpoint inhibitors (ICIs), Hu et al. established a mouse model of skin commensal bacteria-driven irAEs that recapitulated human cutaneous disease pathology. Combination of anti-CTLA-4 and skin neo-colonization with a commensal S. epidermidis caused a commensal-specific inflammatory CD4+ and CD8+ T cell response dependent on IL-17 production in skin. Initial CTLA-4 blockade also primed aberrant memory T cell responses against S. epidermidis, perpetuating inflammatory memory responses following cessation of ICI treatment.
Contributed by Katherine Turner
ABSTRACT: Immune checkpoint inhibitors (ICIs) are essential components of the cancer therapeutic armamentarium. While ICIs have demonstrated remarkable clinical responses, they can be accompanied by immune-related adverse events (irAEs). These inflammatory side effects are of unclear etiology and impact virtually all organ systems, with the most common being sites colonized by the microbiota such as the skin and gastrointestinal tract. Here, we establish a mouse model of commensal bacteria-driven skin irAEs and demonstrate that immune checkpoint inhibition unleashes commensal-specific inflammatory T cell responses. These aberrant responses were dependent on production of IL-17 by commensal-specific T cells and induced pathology that recapitulated the cutaneous inflammation seen in patients treated with ICIs. Importantly, aberrant T cell responses unleashed by ICIs were sufficient to perpetuate inflammatory memory responses to the microbiota months following the cessation of treatment. Altogether, we have established a mouse model of skin irAEs and reveal that ICIs unleash aberrant immune responses against skin commensals, with long-lasting inflammatory consequences.
Author Info: (1) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. National Cancer Insti
Author Info: (1) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. National Cancer Institute, Medical Oncology Fellowship Program, NIH, Bethesda, MD (2) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. (3) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. (4) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. (5) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. (6) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. (7) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. (8) Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892. Microbiome Program, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892.
