Dual Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Inhibition Elicits Antitumor Immunity and Enhances Programmed Cell Death-1 Checkpoint Blockade in Hepatocellular Carcinoma.
Haijing Deng,Anna Kan,Ning Lyu,Luwen Mu,Yi Han,Longzhong Liu,Yanyu Zhang,Youfa Duan,Shuangye Liao,Shaolong Li,Qiankun Xie,Tianxiao Gao,Yanrong Li,Zhenfeng Zhang,Ming Zhao +14 more
TLDR
Inhibition of vascular endothelial growth factor receptor and FGFR augmented the efficacy of anti-PD-1 antibodies and led to long-term immune memory formation, while synergistically modulating the TME and enhancing the cytotoxic effect of T cells.Abstract:
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.read more
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Combination strategies with PD-1/PD-L1 blockade: current advances and future directions
TL;DR: In this article , the authors summarized the synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other therapies, and focused on the advances of αPD- 1/PD L 1-based immunomodulatory strategies in clinical studies.
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Combination strategies with PD-1/PD-L1 blockade: current advances and future directions
TL;DR: In this paper , the authors summarized the synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other therapies, and focused on the advances of αPD- 1/PD L 1-based immunomodulatory strategies in clinical studies.
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Inhibition of FGF-FGFR and VEGF-VEGFR signalling in cancer treatment
TL;DR: In this paper, the authors discuss the FGF-FGFR signalling pathway, the VEGF-VEGFR signaling pathway, and the rationale of combining these two signalling pathways and recent small-molecule FGFR/veGFR inhibitors based on clinical trials.
Journal ArticleDOI
Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma.
Haijing Deng,Anna Kan,Ning Lyu,Meng He,Xin Huang,Shuang Qiao,Shaolong Li,Wenhua Lu,Qiankun Xie,Huiming Chen,Jinfa Lai,Qifeng Chen,Xiongying Jiang,Shousheng Liu,Zhenfeng Zhang,Ming Zhao +15 more
TL;DR: In this article, the effect of neutrophil activation on PD-L1+ neutrophils in tumor micro-environment (TME) was examined with RNA sequencing and multicolor flow cytometry analysis in patient samples, subcutaneous and orthotopic mouse models.
Journal ArticleDOI
Initial Experience of Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma in Real-World Clinical Practice.
Hideki Iwamoto,Shigeo Shimose,Yu Noda,Tomotake Shirono,Takashi Niizeki,Masahito Nakano,Shusuke Okamura,Naoki Kamachi,Hiroyuki Suzuki,Miwa Sakai,Akira Kajiwara,Satoshi Itano,Masatoshi Tanaka,Taizo Yamaguchi,Ryoko Kuromatsu,Hironori Koga,Takuji Torimura +16 more
TL;DR: In this paper, the authors evaluated the efficacy and safety of atezolizumab plus bevacizumaab for patients with hepatocellular carcinoma (HCC).
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Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma
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TL;DR: Treatment with cabozantinib resulted in longer overall survival and progression‐free survival than placebo among patients with previously treated advanced hepatocellular carcinoma, and the rate of high‐grade adverse events in the cabozaninib group was approximately twice that observed in the placebo group.
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