By Lynn McCain

Dr. Gabriel Nuñez, the Paul de Kruif Professor of Pathology, and his laboratory colleagues recently published breakthrough research results in the journal Science , describing how his team identified new key roles of the gut’s microbiota in the development of colitis.

Patients receiving checkpoint inhibitors as part of cancer therapy often develop colitis, a severe adverse reaction that can cause patients to discontinue their cancer treatments. Researchers were previously unable to identify why colitis developed as when checkpoint inhibitors were tested on the mice in the laboratory, they did not develop colitis. The idea that sparked this ground-breaking research was the fact that laboratory mice are kept in sterile environments, but people are not. Could there be something in the environment that changed the makeup of the gut’s microbiota, thereby making them susceptible to colitis when given a checkpoint inhibitor?

To explore this possibility, Dr. Bernard Lo, a member of the Nuñez laboratory, transferred the microbiota from caught wild mice to laboratory mice and administered anti-CTLA-4 antibodies, which are used in the clinic to promote anti-tumor responses. The microbiota from wild-caught mice, unlike that from laboratory mice, induced colitis, just as occurred in people. The microbiota transfer resulted in the laboratory mice developing colitis following the administration of checkpoint inhibitor anti-CTLA-4 antibodies. This exciting discovery led to a series of experiments, many of which are ongoing, to determine which microbiota differences were important and the pathways that were activated leading to the development of colitis.

They discovered that mice with the wild-mouse microbiota, but lacking the receptor FcγR that is recognized by the Fc portion of most antibodies, including CTLA-4 antibodies, were highly resistant to colitis. Consistent with the latter, administration of a Fc-null CTLA-4 antibody retained anti-tumor activity but did not induce colitis. Thus, Nuñez reports that an Fc-null anti-CTLA4 antibody, either alone or in combination with PD-1 or PD-L1 blockade, can effectively stimulate anti-cancer immune responses without inducing intestinal inflammation, opening the doors to novel areas of research that may provide new therapeutic opportunities to cancer patients without having the deleterious effects of colitis.

This study was also reported on by the Rogel Cancer Center and the full study can be found at:

Citation: Bernard C. Lo, Ilona Kryczek, Jiali Yu, Linda Vatan, Roberta Caruso, Masanori Matsumoto, Yosuke Sato, Michael H. Shaw, Naohiro Inohara, Yuying Xie, Yu Leo Lei, Weiping Zou, Gabriel Nuñez. Microbiota-dependent activation of CD4+ T cells induces CTLA-4 blockage-associated colitis via Fcγ receptors. Science 2024; 383(6678):pages 62-70. doi.org/10.1126/science.adh8342.