YIV‑906 potentiated anti‑PD1action against hepatocellular carcinoma by enhancing adaptive and innate immunity in the tumor microenvironment

Yang, Xiaochen and Lam, Wing and Jiang, Zaoli and Guan, Fulan and Han, Xue and Hu, Rong and Cai, Wei and Cheng, William and Liu, Shwu-Huey and Cheng, Peikwen and Cai, Yuping and Rattray, Nicholas and Johnson, Caroline and Chen, Lieping and Cheng, Yung-Chi (2021) YIV‑906 potentiated anti‑PD1action against hepatocellular carcinoma by enhancing adaptive and innate immunity in the tumor microenvironment. Scientific Reports, 11 (1). 13482. ISSN 2045-2322

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    YIV-906 (PHY906) is a standardized botanical cancer drug candidate developed with a systems biology approach—inspired by a traditional Chinese herbal formulation, historically used to treat gastrointestinal symptoms including diarrhea, nausea and vomiting. In combination with chemotherapy and/or radiation therapy, preclinical and clinical results suggest that YIV-906 has the potential to prolong survival and improve quality of life for cancer patients. Here, we demonstrated that YIV-906 plus anti-PD1 could eradicate all Hepa 1–6 tumors in all tumor bearing mice. YIV-906 was found to have multiple mechanisms of action to enhance adaptive and innate immunity. In combination, YIV-906 reduced PD1 or counteracted PD-L1 induction caused by anti-PD1 which led to higher T-cell activation gene expression of the tumor. In addition, YIV-906 could reduce immune tolerance by modulating IDO activity and reducing monocytic MDSC of the tumor. The combination of anti-PD1 and YIV-906 generated acute inflammation in the tumor microenvironment with more M1-like macrophages. YIV-906 could potentiate the action of interferon gamma (IFNg) to increase M1-like macrophage polarization while inhibiting IL4 action to decrease M2 macrophage polarization. Flavonoids from YIV-906 were responsible for modulating IDO activity and potentiating IFNg action in M1-like macrophage polarization. In conclusion, YIV-906 could act as an immunomodulator and enhance the innate and adaptive immune response and potentiate anti-tumor activity for immunotherapies to treat cancer.

    ORCID iDs

    Yang, Xiaochen, Lam, Wing, Jiang, Zaoli, Guan, Fulan, Han, Xue, Hu, Rong, Cai, Wei, Cheng, William, Liu, Shwu-Huey, Cheng, Peikwen, Cai, Yuping, Rattray, Nicholas ORCID logoORCID: https://orcid.org/0000-0002-3528-6905, Johnson, Caroline, Chen, Lieping and Cheng, Yung-Chi;