Immune checkpoint inhibitors unleash pathogenic immune responses against the microbiota

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.

Automated summary

This study investigates the impact of immune checkpoint inhibitors (ICIs) on skin immune-related adverse events (irAEs) caused by commensal bacteria and establishes a mouse model to validate this effect. The results demonstrate that ICIs can unleash inflammatory T cell responses against commensal-specific bacteria, leading to skin inflammation. Importantly, these aberrant responses can persistently affect commensal bacteria even after the cessation of treatment.