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Oncotarget. 2017 Jul 25;8(30):48959-48971. doi: 10.18632/oncotarget.16900.

Identification of a novel PD-L1 positive solid tumor transplantable in HLA-A*0201/DRB1*0101 transgenic mice.

Author information

1
University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-gGreffon-Tumeur, Ingénierie Cellulaire et Génique, F-25000 Besançon, France.
2
LabEx LipSTIC, F-25000 Besançon, France.
3
Platform for Transfer to Cancer Biology, Centre Georges-François Leclerc, 21000 Dijon, France.
4
University Hospital of Rouen, INSERM UMR1245, Institute for Research and Innovation in Biomedicine, 76183 Rouen, France.
5
Department of Medical Oncology, University Hospital of Besançon, 25000 Besançon, France.
6
INSERM/UPS, US006/CREFRE, Department of Histopathology, University Hospital of Purpan, 31000 Toulouse, France.
7
Department of Genetics, University Hospital of Rouen, Normandy Centre for Genomic and Personalized Medicine, 76183 Rouen, France.
8
Department of Pathology, University Hospital of Besançon, 25000 Besançon, France.

Abstract

HLA-A*0201/DRB1*0101 transgenic mice (A2/DR1 mice) have been developed to study the immunogenicity of tumor antigen-derived T cell epitopes. To extend the use and application of this mouse model in the field of antitumor immunotherapy, we described a tumor cell line generated from a naturally occurring tumor in A2/DR1 mouse named SARC-L1. Histological and genes signature analysis supported the sarcoma origin of this cell line. While SARC-L1 tumor cells lack HLA-DRB1*0101 expression, a very low expression of HLA-A*0201 molecules was found on these cells. Furthermore they also weakly but constitutively expressed the programmed death-ligand 1 (PD-L1). Interestingly both HLA-A*0201 and PD-L1 expressions can be increased on SARC-L1 after IFN-γ exposure in vitro. We also obtained two genetically modified cell lines highly expressing either HLA-A*0201 or both HLA-A*0201/ HLA-DRB1*0101 molecules referred as SARC-A2 and SARC-A2DR1 respectively. All the SARC-L1-derived cell lines induced aggressive subcutaneous tumors in A2DR1 mice in vivo. The analysis of SARC-L1 tumor microenvironment revealed a strong infiltration by T cells expressing inhibitory receptors such as PD-1 and TIM-3. Finally, we found that SARC-L1 is sensitive to several drugs commonly used to treat sarcoma and also susceptible to anti-PD-L1 monoclonal antibody therapy in vivo. Collectively, we described a novel syngeneic tumor model A2/DR1 mice that could be used as preclinical tool for the evaluation of antitumor immunotherapies.

KEYWORDS:

HLA transgenic mouse; PD-L1; T cells; cancer immunotherapy; sarcoma

PMID:
28430664
PMCID:
PMC5564740
DOI:
10.18632/oncotarget.16900
[Indexed for MEDLINE]
Free PMC Article

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