Microbiota-dependent activation of CD4 + T cells induces CTLA-4 blockade–associated colitis via Fcγ receptors
2024; American Association for the Advancement of Science; Volume: 383; Issue: 6678 Linguagem: Inglês
10.1126/science.adh8342
ISSN1095-9203
AutoresBernard C. Lo, Ilona Kryczek, Jiali Yu, Linda Vatan, Roberta Caruso, Masanori Matsumoto, Yosuke Sato, Michael H. Shaw, Naohiro Inohara, Yuying Xie, Yu L. Lei, Weiping Zou, Gabriel Núñez,
Tópico(s)Cancer Immunotherapy and Biomarkers
ResumoImmune 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 IFNγ-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.
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