Microbiota-dependent activation of CD4+ T cells induces CTLA-4 blockade-associated colitis via Fcγ receptors.
- Resource Type
- Article
- Authors
- Lo, Bernard C.; Kryczek, Ilona; Jiali Yu; Vatan, Linda; Caruso, Roberta; Masanori Matsumoto; Yosuke Sato; Shaw, Michael H.; Naohiro Inohara; Yuying Xie; Yu Leo Lei; Weiping Zou; Núñez, Gabriel,
- Source
- Science; 1/5/2024, Vol. 383 Issue 6678, p62-70, 9p, 5 Diagrams
- Subject
- T cells
Colitis
Regulatory T cells
Cytotoxic T lymphocyte-associated molecule-4
Drug side effects
Programmed cell death 1 receptors
- Language
- ISSN
- 00368075
Immune checkpoint inhibitors can stimulate antitumor immunity but can 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 IFNg-producing CD4+ T cells and depletion of peripherally induced regulatory T cells through Fcγ receptor signaling. Accordingly, anti-CTLA-4 nanobodies that lack an Fc domain can promote antitumor responses without triggering colitis. This work suggests a strategy for mitigating gut irAEs while preserving antitumor stimulating effects of CTLA-4 blockade. [ABSTRACT FROM AUTHOR]