Microbiota-dependent activation of CD4+ T cells induces CTLA-4 blockade-associated colitis via Fc? receptors

Immune checkpoint inhibitors can stimulate anti-tumor immunity, but also induce toxicities termed immune-related adverse events (irAEs). Colitis is a common and severe irAE that can lead to treatment discontinuation. Mechanistic understanding of gut irAEs has been hampered because robust colitis is not observed in laboratory mice treated with checkpoint inhibitors. We report here that this limitation can be overcome by using mice harboring the microbiota of wild-caught mice, which develop overt colitis following treatment with anti-CTLA-4 antibodies. Intestinal inflammation is driven by unrestrained activation of IFNgamma-producing CD4+ T cells and depletion of peripherally induced regulatory T cells through Fcgamma receptor signaling. Accordingly, anti-CTLA-4 nanobodies that lack an Fc domain can promote anti-tumor responses without triggering colitis. This work suggests a strategy for mitigating gut irAEs while preserving anti-tumor stimulating effects of CTLA-4 blockade.