YIV-906 potentiated anti-PD1 action against hepatocellular carcinoma by enhancing adaptive and innate immunity in the tumor microenvironment

Abstract

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.

Frontier progress of the combination of modern medicine and traditional Chinese medicine in the treatment of hepatocellular carcinoma

“…In addition, the combination of TCM with ICIs, other chemotherapeutic drugs and molecular targeted drugs improved the antitumor effect of the drugs [ 108 – 113 ] (Additional file 1 : Table S1).…”

Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook

“…Moreover, Yang and his team reported that the anti-tumor activity of anti-PD1 was markedly enhanced in combination of YIV-906 via promoting the adaptive and innate immune responses. 279 In terms of single herbs, Kanglaite as an extract from Coix seeds also enhanced the suppressive effects of cisplatin on HCC cells, exhibiting synergistic effects in the combination with conventional treatments. 280 Of significant mention is icaritin, a prenylflavonoid derivative from epimedium.…”

YIV-906 enhances nuclear factor of activated T-cells (NFAT) activity of T cells and promotes immune checkpoint blockade antibody action and CAR T-cell activity

“…In the presence of neoantigens caused by anti-cancer agents, YIV-906 could potentiate innate and/or adaptive immunity potentiation through multiple mechanisms of action. To enhance innate immunity, YIV-906 can potentiate interferon-gamma (IFNg) action to induce M1-like macrophage polarization simultaneously inhibiting IL4 action to induce M2 macrophage polarization ( Lam et al, 2015 ; Yang et al, 2021 ). To enhance adaptive immunity, YIV-906 reduces PD1 or counteracts PD-L1 induction caused by anti-PD1, leading to higher T-cell activation-associated gene expression in the tumor ( Yang et al, 2021 ).…”

“…To enhance innate immunity, YIV-906 can potentiate interferon-gamma (IFNg) action to induce M1-like macrophage polarization simultaneously inhibiting IL4 action to induce M2 macrophage polarization ( Lam et al, 2015 ; Yang et al, 2021 ). To enhance adaptive immunity, YIV-906 reduces PD1 or counteracts PD-L1 induction caused by anti-PD1, leading to higher T-cell activation-associated gene expression in the tumor ( Yang et al, 2021 ). To help overcome immune suppression, YIV-906 reduces immune tolerance by modulating IDO activity and reducing monocytic MDSC in the tumor ( Yang et al, 2021 ).…”