Bifidobacterium producing interferon-γ induces tumor shrinkage in combination with anti-PD-1 blockade in syngeneic mouse model
Shiro Kataoka1*, Satoshi Kobayashi1, Yuji Seki1, Koichiro Shioya1, Li Wang1, Yuko Shimatani1, Takaaki Nakamura1, Shun'ichiro Taniguchi2
1Anaeropharma Science, Inc., 19-8, Nihonbashi Kabuto-cho, Chuo-ku, Tokyo 103-0026, Japan; 2Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan
Interferon-γ is a cytokine having antitumor activity and has been developed as an anticancer drug in multiple cancer indications but failed due to its limited efficacy and severe adverse events. In several publications, IFN-γ has been clarified to induce PD-L1 expression in tumors. Upregulation of PD-L1 renders tumor resistance to cytotoxic T cell and it may cause the limited efficacy of the IFN-γ treatment.
Here in the present report, in an aim of decreasing adverse events, we have created recombinant Bifidobacterium, which is a non-pathogenic anaerobic bacterium modified to secrete IFN-γ specifically inside solid tumor. Both human and murine IFN-γ have growth inhibitory activities against tumor cells and CXCL10 inducing activity for T cells. On the other hand, IFN-γ induced immune suppressive molecule PD-L1 on tumor cell surface. For overcoming the immunosuppressive situation by PD-L1 expression, combination of IFN-γ producing Bifidobacterium and anti-murine PD-1 antibody is investigated. This combination significantly suppresses tumor growth whereas each single treatment moderately contributes to tumor suppression in a CT26 bearing syngeneic mouse model. In addition, ELISA assay indicated that there are substantial IFN-γ detected in tumor tissue but none of them are detectable in blood and other organs. All in together, combination treatment with IFN-γ producing Bifidobacterium and anti-PD-1 antibody offers a promising anti-tumor approach.
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- Mimura K., Cancer Sci., 2018 Jan;109(1):43-53. PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer.