Anti-CTLA-4 nanobodies promote antitumor immunity without inducing colitis in mice

Microbiota-reactive T cells trigger colitis in mice harboring the microbiota of wild-caught mice following CTLA-4 blockade, according to a new study that reveals a major mechanism by which anti-CTLA-4 antibodies induce inflammatory toxicities during antitumor immune checkpoint inhibitor therapies. The findings could advance the development of next-generation CTLA-4 inhibitors that promote antitumor immune responses without triggering intestinal disease. Cancer immunotherapies with immune checkpoint inhibitors are widely used to promote antitumor immune responses in a range of human cancers. However, they can also lead to inflammatory toxicities known as immune-related adverse events (irAEs). Colitis – a chronic intestinal disease characterized by inflammation of the colon’s inner lining – is a common and severe irAE that can result in treatment discontinuation, particularly in patients treated with antibodies targeting the checkpoint inhibitor protein CTLA-4. However, because conventionally raised laboratory mice are highly resistant to intestinal inflammation following treatment with antibodies targeting immune checkpoints, the immunological mechanisms and role of the gut microbiota underlying immune checkpoint blockade (ICB)-induced colitis in patients aren’t fully understood. Here, Bernard Lo and colleagues investigated whether mice harboring a referenced gut microbiota originally derived from wild-caught mice (wild mouse microbiome-reconstituted or WildR mice) would be a more suitable model system for ICB-induced colitis. Lo et al. found that, unlike conventionally raised specific pathogen-free mice, WildR mice develop robust colitis after treatment with anti-CTLA-4 antibodies and that the inflamed tissues in these mice display several hallmark features of clinical ICB-associated colitis. The findings show that CTLA-4 blockade-induced colitis in mice is dependent on gut microbiota composition and driven by unrestrained activation of a subset of the regulatory T cells in the gut by receptors recognizing the Fc domain of the anti-CTLA-4 antibodies used in CTLA-4 ICB therapies. Lo et al. show that anti-CTLA-4 nanobodies lacking the Fc domain can promote antitumor responses without inducing colitis, which may provide a strategy for mitigating gut IrAEs while preserving the antitumor effects of CTLA-4 blockade therapies.