4.7 Article

Bufalin stimulates antitumor immune response by driving tumor-infiltrating macrophage toward M1 phenotype in hepatocellular carcinoma

期刊

出版社

BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2021-004297

关键词

liver neoplasms; tumor microenvironment; macrophages; immunotherapy; drug therapy; combination

资金

  1. National Natural Science Foundation of China [82074154, 81774240, 81874436, 81904017, 81904117]
  2. Three-year Action Plan for the Development of Chinese Medicine in Shanghai [ZY (2018-2020)-CCCX-2003-01]
  3. Shanghai Key Clinical Specialty Construction Project [shslczdzk01201]
  4. Shanghai Shuguang Hospital [SGXZ-201904]
  5. Youth Tip-top Talent program in Shanghai
  6. Shanghai University of Traditional Chinese Medicine

向作者/读者索取更多资源

This study found that bufalin can promote the polarization of tumor-infiltrating macrophages (TIMs) towards the tumor-inhibitory M1 phenotype to improve the efficacy of immunotherapy for hepatocellular carcinoma (HCC). Bufalin inhibits the overexpression of p50 nuclear factor kappa B (NF-kappa B) factor and activates the NF-kappa B signaling pathway, resulting in the production of immunostimulatory cytokines and the activation of antitumor T cell immune response. Bufalin also enhances the antitumor activity of anti-PD-1 antibody in HCC.
Background Immunotherapy for hepatocellular carcinoma (HCC) exhibits limited clinical efficacy due to immunosuppressive tumor microenvironment (TME). Tumor-infiltrating macrophages (TIMs) account for the major component in the TME, and the dominance of M2 phenotype over M1 phenotype in the TIMs plays the pivotal role in sustaining the immunosuppressive character. We thus investigate the effect of bufalin on promoting TIMs polarization toward M1 phenotype to improve HCC immunotherapy. Methods The impact of bufalin on evoking antitumor immune response was evaluated in the immunocompetent mouse HCC model. The expression profiling of macrophage-associated genes, surface markers and cytokines on bufalin treatment in vitro and in vivo were detected using flow cytometry, immunofluorescence, western blot analysis, ELISA and RT-qPCR. Cell signaling involved in M1 macrophage polarization was identified via the analysis of gene sequencing, and bufalin-governed target was explored by immunoprecipitation, western blot analysis and gain-and-loss of antitumor immune response. The combination of bufalin and antiprogrammed cell death protein 1 (anti-PD-1) antibody was also assessed in orthotopic HCC mouse model. Results In this study, we showed that bufalin can function as an antitumor immune modulator that governs the polarization of TIMs from tumor-promoting M2 toward tumor-inhibitory M1, which induces HCC suppression through the activation of effector T cell immune response. Mechanistically, bufalin inhibits overexpression of p50 nuclear factor kappa B (NF-kappa B) factor, leading to the predominance of p65-p50 heterodimers over p50 homodimers in the nuclei. The accumulation of p65-p50 heterodimers activates NF-kappa B signaling, which is responsible for the production of immunostimulatory cytokines, thus resulting in the activation of antitumor T cell immune response. Moreover, bufalin enhances the antitumor activity of anti-PD-1 antibody, and the combination exerts synergistic effect on HCC suppression. Conclusions These data expound a novel antitumor mechanism of bufalin, and facilitate exploitation of a new potential macrophage-based HCC immunotherapeutic modality.

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