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

Author:

Lo Bernard C.1ORCID,Kryczek Ilona23ORCID,Yu Jiali23ORCID,Vatan Linda23ORCID,Caruso Roberta1ORCID,Matsumoto Masanori1ORCID,Sato Yosuke4ORCID,Shaw Michael H.4ORCID,Inohara Naohiro1ORCID,Xie Yuying5,Lei Yu Leo6ORCID,Zou Weiping123ORCID,Núñez Gabriel1ORCID

Affiliation:

1. Department of Pathology and Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.

2. Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.

3. Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.

4. Takeda Pharmaceuticals International Co., Cambridge, MA 02139 USA.

5. Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI 48824, USA

6. Department of Periodontics and Oral Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48104, USA

Abstract

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 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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