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

• 成果类型: Article
• 署名作者: Lo, Bernard C.; Kryczek, Ilona; Yu, Jiali; Vatan, Linda; Caruso, Roberta; Matsumoto, Masanori; Sato, Yosuke; Shaw, Michael H.; Inohara, Naohiro; Xie, Yuying; Lei, Yu Leo; Zou, Weiping; Nunez, Gabriel
• 署名单位: University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Takeda Pharmaceutical Company Ltd; Takeda Pharmaceuticals International, Inc.; Michigan State University; University of Michigan System; University of Michigan
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11462
• DOI: 10.1126/science.adh8342
• 发表日期: 2024-01-05
• 页码: 62-70
• 关键词: antitumor-activity; effector

摘要

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 IFN gamma-producing CD4(+) T cells and depletion of peripherally induced regulatory T cells through Fc gamma 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.