Modulation of the tumour microenvironment in hepatocellular carcinoma by tyrosine kinase inhibitors: from modulation to combination therapy targeting the microenvironment

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Tyrosine kinase inhibitors (TKIs) remain the backbone of systematic therapy for advanced hepatocellular carcinoma. Sorafenib and lenvatinib are currently approved as first-line therapeutic drugs, and regorafenib and cabozantinib are applied as second-line treatments. With inhibition of angiogenesis as the main target, TKIs exert a profound effect on the tumour microenvironment (TME). The TME is a complex mixture of cellular and noncellular components surrounding the tumour mass, and is associated with tumour progression partially through the epithelial–mesenchymal transition. Specifically, the TME of HCC is characterized by profound extracellular matrix remodelling and an immunosuppressive microenvironment. The purpose of this review is to provide a summary of TME remodelling mediated by four Food and Drug Administration approved TKIs in HCC and thus summarize the rationale and potential targets for combination therapy. The modulatory effect of TKIs on the TME of HCC was reported to enhance the antitumour effect of TKIs through pyroptosis of macrophages and subsequent natural killer cell activation, T cell activation, regulatory T cell reduction in HCC. Meanwhile, TKIs also induce drug resistance via M2 polarization and accumulation, recruitment of tumour-associated neutrophils, and induction of the epithelial–mesenchymal transition. In conclusion, the effect of TKIs on TME can enhance its antitumour effect, but might also partially contribute to the drug resistance that hinders the progression of TKIs as treatment for HCC. Additionally, the effect of TKIs also provides the rationale for combination therapy, including combining TKIs with immune checkpoint inhibitors, to facilitate increased drug efficacy of TKIs.

Conversion surgery for advanced hepatocellular carcinoma after combination treatment of lenvatinib and camrelizumab: a case report

“…In this study, we reported a case in which conversion therapy for initially unresectable HCC was successfully achieved following the combination treatment of lenvatinib and camrelizumab. After searching the ClinicalTrials.gov database, we found several clinical trials that used lenvatinib and camrelizumab combination for advanced HCC, including NCT04443309, NCT04627012, and NCT04639284 [ 23 , 24 ]. However, it is essential to initiate more clinical trials to evaluate the efficacy, safety, and conversion rate of this novel combination regimen for HCC and to investigate suitable markers to identify the target population.…”

Long term complete response of advanced hepatocellular carcinoma to glypican-3 specific chimeric antigen receptor T-Cells plus sorafenib, a case report

“…Sorafenib is recommended as a first-line oral systemic therapy for HCC which has been reported to have immune-modulatory effects (32)(33)(34). It can modulate the cytokine phenotype of macrophage toward a profile that promotes the function of immune effector cells.…”

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

“…TKIs can also activate immune cells, and there is no significant overlap in the toxicity of TKIs and ICIs. 233 A phase III clinical trial showed that axitinib combined with pembrolizumab significantly prolonged the survival of RCC patients, compared with sunitinib alone. 234 Clinical trials of lenvatinib combined with pembrolizumab for endometrial cancer, HCC, and RCC have also shown encouraging safety and efficacy.…”