Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Contributed by Mark M. Davis, November 13, 2017 (sent for review July 24, 2017; reviewed by Jeffrey J. Molldrem and David M. Sansom)
Significance
The major stumbling block in the use of checkpoint inhibitors for cancer treatment is the severe autoimmunity that often results. In this study, we found the toxicity of a checkpoint blockade antibody can be ameliorated via administration of Bifidobacterium, a widely available probiotic. These results suggest that it may be possible to mitigate the autoimmunity caused by anti–CTLA-4 and perhaps other checkpoint inhibitors by manipulating gut microbiota.
Abstract
Antibodies that attenuate immune tolerance have been used to effectively treat cancer, but they can also trigger severe autoimmunity. To investigate this, we combined anti–CTLA-4 treatment with a standard colitis model to give mice a more severe form of the disease. Pretreatment with an antibiotic, vancomycin, provoked an even more severe, largely fatal form, suggesting that a Gram-positive component of the microbiota had a mitigating effect. We then found that a commonly used probiotic, Bifidobacterium, could largely rescue the mice from immunopathology without an apparent effect on antitumor immunity, and this effect may be dependent on regulatory T cells.
Footnotes
- ↵1To whom correspondence may be addressed. Email: wangfeng16{at}sjtu.edu.cn or mmdavis{at}stanford.edu.
Author contributions: F.W. and M.M.D. designed research; F.W. performed research; Q.Y. and L.C. contributed reagents/analytic tools; F.W. analyzed data; and F.W. and M.M.D. wrote the paper.
Reviewers: J.J.M., University of Texas MD Anderson Cancer Center; and D.M.S., University College London Institute of Immunity and Transplantation.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1712901115/-/DCSupplemental.
Published under the PNAS license.
Bifidobacterium mitigates αCTLA-4 immunopathology
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- Immunology and Inflammation
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