Abstract

Cryptotanshinone (CT), a purified compound initially isolated from the dried roots of Salvia militorrhiza. Bunge, exhibits cytotoxic antitumor effects on many tumors. We have shown that CT possesses the dual capacities to concomitantly inhibit the proliferation of lung cancer cells and promote the generation of antitumor immunity. In this study, we investigated whether CT could be used to treat hepatocellular carcinoma (HCC) using a mouse Hepa1-6 model. CT inhibited the proliferation of mouse hepatoma (Hepa1-6) cells in vitro by inducing Hepa1-6 cells apoptosis through the JAK2/STAT3 signaling pathway. In addition, CT activated macrophages and polarized mouse bone marrow-derived macrophages (BMM) toward an M1 phenotype in vitro, which depended on the TLR7/MyD88/NF-κB signaling pathway. Furthermore, CT significantly inhibited the growth of syngeneic Hepa1-6 hepatoma tumors, and, in combination with anti-PD-L1 cured Hepa1-6-bearing mice with the induction of long-term anti-Hepa1-6 specific immunity. Immunoprofiling of treated Hepa1-6-bearing mice revealed that CT-promoted activation of tumor-infiltrating macrophages and dendritic cells, induction of antitumor T cell response, and infiltration of effector/memory CD8 T cells in the tumor tissue. Importantly, the immunotherapeutic effects of CT and anti-PD-L1 depended on the presence of CD8 T cells. Thus, CT and anti-PD-L1 may provide an effective immunotherapeutic regimen for human HCC based on a combination of cytotoxic effects and induction of tumor-specific immunity.

Highlights

  • The antitumor effects of checkpoint inhibitors have revealed the importance of immune-mediated antitumor defenses [1]

  • We investigated the potential antiproliferative effect of CT on Hepa1-6 cells and found that CT inhibited the growth of Hepa1-6 cells by inducing apoptosis through blockade of the JAK2/STAT3 signaling pathway

  • We developed a successful immunotherapeutic vaccination regimen of Hepa1-6 tumors based on cytotoxic effect and the immune-activating effect of CT with potentiation of the antitumor therapeutic effects by addition of the checkpoint inhibitor

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Summary

Introduction

The antitumor effects of checkpoint inhibitors have revealed the importance of immune-mediated antitumor defenses [1]. Macrophages are crucial contributors to innate immunity and function as antigen-presenting cells (APCs). Macrophages are heterogeneous and can exert opposing functions that promote tumor development and progression [2]. Tumor associated macrophages (TAMs) displaying the M2 phenotype promote tumor growth and metastasis. The M1 counterpart possesses proinflammatory and tumor suppressive properties [2, 3]. Macrophages display plasticity and change their functional profiles in response to environmental stimuli. The reprogramming of macrophages toward M1 phenotype is believed to be a key target of antitumor immunotherapy [4]

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