Skin microbiota drive checkpoint inhibitor toxicity in a genetically autoimmune-susceptible

Patients with pre-existing autoimmune disease are at greatest risk of developing side effects to immune checkpoint inhibitor (ICI) therapy presenting a growing challenge for patient care. Here, we report a model wherein genetic autoimmune susceptibility coupled with skin microbiota led to ICI-induced systemic toxicity. Treatment of young Act1-/- mice, a model of subclinical autoimmunity, with ICI resulted in attenuated weight gain, pancreatic inflammation, eczematous dermatitis, and increased circulating IgG and autoantibodies. ICI toxicity was attenuated with topical antibiotic treatment, and germ free (GF) Act1-/- mice do not develop these side effects, indicating that microbiota is necessary for this phenotype. Co-housing GF and specified pathogen free (SPF) Act1-/- mice was permissive for ICI toxicity. However, colonization of GF Act1-/- mice with intestinal microbes failed to render GF Act1-/- mice susceptible to ICI autoimmunity, suggesting that an alternate source of microbes was required. Notably, the skin microbiota rendered GF Act1-/- mice susceptible to ICI toxicity when transferred from strain-matched SPF mice. Shotgun metagenomic sequencing of the skin donor inoculum indicated a three-member community: Staphylococcus epidermidis, Staphylococcus xylosus, and Enterococcus faecalis. In a subcutaneous tumor model, topical antibiotics were capable of decoupling ICI-induced toxicity from anti-tumor efficacy in SPF Act1-/- mice.