Colitis is an immune-related adverse event that is commonly observed in patients treated with checkpoint blockade, but not in pathogen-free laboratory mice. By transplanting lab mice with a gut microbiome from wild-caught mice, Lo et al. were able to recapitulate anti-CTLA-4-induced colitis. Using this WildR model, they found that intestinal inflammation was mediated by both the enhanced activation of IFNγ-producing CD4+ Th1 cells and the depletion of RORγt+ peripherally induced Tregs through FcγR engagement in the gut. Using anti-CTLA-4 antibodies that lacked a functional Fc domain promoted antitumor activity in different tumor models without triggering colitis, even in combination with PD-1 blockade.
Contributed by Lauren Hitchings
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.
Author Info: (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.
Author Info: (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. Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. (3) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. (4) Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. (5) Department of Pathology and Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. (6) Department of Pathology and Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. (7) Takeda Pharmaceuticals International Co., Cambridge, MA 02139 USA. (8) Takeda Pharmaceuticals International Co., Cambridge, MA 02139 USA. (9) Department of Pathology and Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. (10) Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI 48824, USA. (11) Department of Periodontics and Oral Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48104, USA. (12) Department of Pathology and Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. (13) Department of Pathology and Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
