Oncotarget

Research Papers:

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

Laurie Rangan, Jeanne Galaine, Romain Boidot, Mohamad Hamieh, Magalie Dosset, Julie Francoual, Laurent Beziaud, Jean-René Pallandre, Elodie Lauret Marie Joseph, Afag Asgarova, Christophe Borg, Talal Al Saati, Yann Godet, Jean Baptiste Latouche, Séverine Valmary-Degano and Olivier Adotévi _

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Oncotarget. 2017; 8:48959-48971. https://doi.org/10.18632/oncotarget.16900

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Abstract

Laurie Rangan1,2, Jeanne Galaine1,2, Romain Boidot3, Mohamad Hamieh4, Magalie Dosset1,2, Julie Francoual4, Laurent Beziaud1,2, Jean-René Pallandre1, Elodie Lauret Marie Joseph1,2, Afag Asgarova1,2,Christophe Borg1,2,5, Talal Al Saati6, Yann Godet1,2, Jean Baptiste Latouche7, Séverine Valmary-Degano8 and Olivier Adotévi1,2,5

1University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-gGreffon-Tumeur, Ingénierie Cellulaire et Génique, F-25000 Besançon, France

2LabEx LipSTIC, F-25000 Besançon, France

3Platform for Transfer to Cancer Biology, Centre Georges-François Leclerc, 21000 Dijon, France

4University Hospital of Rouen, INSERM UMR1245, Institute for Research and Innovation in Biomedicine, 76183 Rouen, France

5Department of Medical Oncology, University Hospital of Besançon, 25000 Besançon, France

6INSERM/UPS, US006/CREFRE, Department of Histopathology, University Hospital of Purpan, 31000 Toulouse, France

7Department of Genetics, University Hospital of Rouen, Normandy Centre for Genomic and Personalized Medicine, 76183 Rouen, France

8Department of Pathology, University Hospital of Besançon, 25000 Besançon, France

Correspondence to:

Olivier Adotévi, email: Olivier.adotevi@univ-fcomte.fr

Keywords: HLA transgenic mouse, PD-L1, sarcoma, T cells, cancer immunotherapy

Received: September 08, 2016     Accepted: March 22, 2017     Published: April 06, 2017

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.


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