期刊
LIVER CANCER
卷 9, 期 3, 页码 338-357出版社
KARGER
DOI: 10.1159/000505695
关键词
Immune checkpoint; Vascular endothelial growth factor A; bFGF; Lenvatinib; Programmed cell death-1 antibodies; Sorafenib; Immunomodulatory; Liver cancer
资金
- National Natural Science Foundation of China [81771956]
- National Natural Science Foundation of Guangdong [2016A030313282, 2017A020215149]
- Eisai
Background and Aims:Combining anti-angiogenic therapy with immune checkpoint blockade with anti-programmed cell death-1 (PD-1) antibodies is a promising treatment for hepatocellular carcinoma (HCC). Tyrosine kinase inhibitors are well-known anti-angiogenic agents and offer potential for combination with anti-PD-1 antibodies. This study investigated the possible underlying immunomodulatory mechanisms of combined therapy.Methods:HCC tissue samples for RNA-sequencing (RNA-seq) were obtained from patients with differential prognoses following anti-PD-1 treatment. Recombinant basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGFA) were used to stimulate T cells following lenvatinib or sorafenib treatment, respectively. T cell function was analyzed by flow cytometry and lactate dehydrogenase assay. In vivo experiments were conducted in murine H22 and Hepa 1-6 competent models of HCC. Local immune infiltration in the tumor microenvironment (TME) was assessed using multicolor flow cytometry. Gene regulation was evaluated by RNA-seq. Microvascular density was measured by immunohistochemistry, and PD-1 ligand (PD-L1) induction was quantified by western blot.Results:The baseline expression of VEGF and fibroblast growth factor (FGF) in patients with progressive disease was significantly higher than in patients achieving stable disease following anti-PD-1 treatment. VEGFA and bFGF significantly upregulated the expression of PD-1, cytotoxic T-lymphocyte-associated protein-4, and Tim-3 on T cells, while inhibiting the secretion of interferon gamma (IFNG) and granzyme B and suppressing T cell cytotoxicity. This immunosuppressive effect was reverted by lenvatinib but not sorafenib. Furthermore, dual lenvatinib/anti-PD-1 antibody therapy led to better antitumor effects than either sorafenib or fibroblast growth factor receptor (FGFR) inhibitor (BGJ398) in H22 murine models of HCC. Combined lenvatinib/anti-PD-1 treatment also led to long-term immune memory formation, while synergistically modulating the TME and enhancing the cytotoxic effect of T cells. Finally, lenvatinib inhibited PD-L1 expression on human umbilical vein endothelial cells, which improved the function of T cells.Conclusions:Inhibition of vascular endothelial growth factor receptor and FGFR augmented the efficacy of anti-PD-1 antibodies. Combined lenvatinib/anti-PD-1 treatment appears to exert antitumor activity by synergistically modulating effector T cell function in the TME and by mutually regulating tumor vessel normalization.
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