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

Laurie Rangan 1, 2, 3 Jeanne Galaine 1, 2, 3 Romain Boidot 4 Mohamad Hamieh 5, 6 Magalie Dosset 1, 2, 3 Julie Francoual 5, 6 Laurent Beziaud 1, 2, 3 Jean-René Pallandre 1 Elodie Lauret Marie Joseph 1, 2, 3 Afag Asgarova 1, 2, 3 Christophe Borg 7, 1, 2, 3 Talal Al Saati 8 Yann Godet 1, 2, 3 Jean Baptiste Latouche 9 Séverine Valmary-Degano 10 Olivier Adotevi 7, 1, 2, 3
1 RIGHT - Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098)
2 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer
3 UBFC - Université Bourgogne Franche-Comté [COMUE]
4 Plateforme de transfert en biologie cancérologique [Dijon]
CEP - Centre d'épidémiologie des populations, UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
5 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
6 CHU Rouen
7 Service d'Oncologie Médicale [CHRU Besançon]
8 UPS CREFRE US006, Service d'Histopathologie
9 Service de génétique [Rouen]
10 Service de Pathologie [CHU Besançon]
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
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01699821
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : vendredi 2 février 2018 - 17:05:57
Dernière modification le : mardi 27 octobre 2020 - 14:35:52

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UNIV-BOURGOGNE | LNC-CADIR | CNRS | UNIV-FCOMTE | INRA | CGFL | EPHE | FNCLCC | UMR645 | COMUE-NORMANDIE | UNIROUEN | LNC-UMR866 | GPMCND | UNIV-MONTPELLIER | INRAE | PSL

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Laurie Rangan, Jeanne Galaine, Romain Boidot, Mohamad Hamieh, Magalie Dosset, et al.. Identification of a novel PD-L1 positive solid tumor transplantable in HLA-A*0201/DRB1*0101 transgenic mice. Oncotarget, Impact journals, 2017, 8 (30), pp.48959-48971. ⟨10.18632/oncotarget.16900⟩. ⟨hal-01699821⟩

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