Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma

Kohei Shigeta, Aya Matsui, Hiroto Kikuchi, Sebastian Klein, Emilie Mamessier, Ivy X. Chen, Shuichi Aoki, Shuji Kitahara, Koetsu Inoue, Ayako Shigeta, Tai Hato, Rakesh R. Ramjiawan, Daniel Staiculescu, Dieter Zopf, Lukas Fiebig, Gabriela S. Hobbs, Alexander Quaas, Simona Dima, Irinel Popescu, Peigen HuangLance L. Munn, Mark Cobbold, Lipika Goyal, Andrew X. Zhu, Rakesh K. Jain, Dan G. Duda

研究成果: Article査読

1 被引用数 (Scopus)

抄録

Background and purpose Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models. Basic procedures We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib-dosed orally at 5, 10 or 20 mg/kg daily-combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer. Main findings Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10- A ligand for CXCR3 expressed on tumor-infiltrating lymphocytes-in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy. Principal conclusions Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.

本文言語English
論文番号e001435
ジャーナルJournal for ImmunoTherapy of Cancer
8
2
DOI
出版ステータスPublished - 2020 11 24
外部発表はい

ASJC Scopus subject areas

  • 免疫アレルギー学
  • 免疫学
  • 分子医療
  • 腫瘍学
  • 薬理学
  • 癌研究

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