Tannins in Terminalia bellirica inhibits hepatocellular carcinoma growth via re-educating tumor-associated macrophages and restoring CD8+T cell function

Abstract

Tumor-associated macrophages (TAMs) are the major immunosuppressive components infiltrating the tumor microenvironment (TME). Targeting TAMs has emerged as a promising strategy to remodel immunosuppressive TME and enhance T-cell mediated anti-tumor immunity for cancer therapy. In this study, we investigate the effect and mechanism of total tannin fraction of Terminalia bellirica (Gaertn.) Roxb. (TB-TF) against hepatocellular carcinoma (HCC) using established Hepa1-6 orthotopic mouse model and murine bone marrow derived macrophage polarization model. Here we showed that TB-TF significantly inhibited orthotopic tumor growth and promoted the polarization of M2-TAMs toward the anti-tumor M1 phenotype in vivo. Further studies showed that TB-TF reversed tumor-conditioned medium induced M2 polarization of macrophages as indicated by increased expression of TNF-α, IL-1β, and iNOS, and decreased expression of Arg-1, thereby re-educating macrophages co-cultured with tumor-conditioned medium into M1 phenotype. In addition, we found that TB-TF also promoted T cell infiltration mediated by chemokines such as CCL5 and CXCL10, and restored the cytotoxic function of CD8⁺T cells as evidenced by upregulated expression of Granzyme B, Perforin, and IFN-γ. Our data suggest TB-TF as a promising anti-cancer agent, mediates its anti-tumor effects via remodeling the tumor immunosuppressive microenvironment, indicating its potential in the immunotherapy for hepatocellular carcinoma.

Keywords: Fibrosis; Hepatocellular carcinoma; Immunomodulation; Macrophage polarization.