Shigeta, Kohei, Matsui, Aya, Kikuchi, Hiroto, Klein, Sebastian ORCID: 0000-0002-2188-9377, Mamessier, Emilie, Chen, Ivy X., Aoki, Shuichi, Kitahara, Shuji ORCID: 0000-0002-2904-0319, Inoue, Koetsu, Shigeta, Ayako, Hato, Tai, Ramjiawan, Rakesh R., Staiculescu, Daniel, Zopf, Dieter, Fiebig, Lukas, Hobbs, Gabriela S., Quaas, Alexander, Dima, Simona, Popescu, Irinel, Huang, Peigen, Munn, Lance L., Cobbold, Mark, Goyal, Lipika, Zhu, Andrew X., Jain, Rakesh K. and Duda, Dan G. (2020). Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma. J. Immunother. Cancer, 8 (2). LONDON: BMJ PUBLISHING GROUP. ISSN 2051-1426

Full text not available from this repository.

Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Shigeta, KoheiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Matsui, AyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kikuchi, HirotoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, SebastianUNSPECIFIEDorcid.org/0000-0002-2188-9377UNSPECIFIED
Mamessier, EmilieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, Ivy X.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aoki, ShuichiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kitahara, ShujiUNSPECIFIEDorcid.org/0000-0002-2904-0319UNSPECIFIED
Inoue, KoetsuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shigeta, AyakoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hato, TaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramjiawan, Rakesh R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Staiculescu, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zopf, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fiebig, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hobbs, Gabriela S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quaas, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dima, SimonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Popescu, IrinelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huang, PeigenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Munn, Lance L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cobbold, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goyal, LipikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhu, Andrew X.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jain, Rakesh K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duda, Dan G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-349554
DOI: 10.1136/jitc-2020-001435
Journal or Publication Title: J. Immunother. Cancer
Volume: 8
Number: 2
Date: 2020
Publisher: BMJ PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2051-1426
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TUMOR MICROENVIRONMENT; GENE-EXPRESSION; SORAFENIB; LIVER; NORMALIZATION; IMMUNOTHERAPY; METABOLITES; INTERFERON; STRATEGIES; THERAPYMultiple languages
Oncology; ImmunologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34955

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item