論文

国際誌
2020年11月

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

Journal for immunotherapy of cancer
  • 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 Huang
  • Lance L Munn
  • Mark Cobbold
  • Lipika Goyal
  • Andrew X Zhu
  • Rakesh K Jain
  • Dan G Duda
  • 全て表示

8
2
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1136/jitc-2020-001435

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.

リンク情報
DOI
https://doi.org/10.1136/jitc-2020-001435
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/33234602
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689089
ID情報
  • DOI : 10.1136/jitc-2020-001435
  • PubMed ID : 33234602
  • PubMed Central 記事ID : PMC7689089

エクスポート
BibTeX RIS