Abstract | BACKGROUND AND PURPOSE: 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.
|
Authors | 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 |
Journal | Journal for immunotherapy of cancer
(J Immunother Cancer)
Vol. 8
Issue 2
(11 2020)
ISSN: 2051-1426 [Electronic] England |
PMID | 33234602
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Copyright | © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. |
Chemical References |
- CXCL10 protein, human
- Chemokine CXCL10
- Phenylurea Compounds
- Programmed Cell Death 1 Receptor
- Pyridines
- regorafenib
|
Topics |
- Animals
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology, therapeutic use)
- CD8-Positive T-Lymphocytes
(drug effects)
- Carcinoma, Hepatocellular
(drug therapy, pathology)
- Cell Line, Tumor
- Chemokine CXCL10
(metabolism)
- Disease Models, Animal
- Humans
- Liver Neoplasms
(drug therapy, pathology)
- Mice
- Phenylurea Compounds
(pharmacology, therapeutic use)
- Programmed Cell Death 1 Receptor
(antagonists & inhibitors)
- Pyridines
(pharmacology, therapeutic use)
|