Identification of a novel PD-L1 positive solid tumor transplantable in HLA-A*0201/DRB1*0101 transgenic mice.
Fiche publication
Date publication
avril 2017
Journal
Oncotarget
Auteurs
Membres identifiés du Cancéropôle Est :
Pr ADOTEVI Olivier, Dr BOIDOT Romain, Pr BORG Christophe, Dr GODET Yann, Dr GALAINE Jeanne
Tous les auteurs :
Rangan L, Galaine J, Boidot R, Hamieh M, Dosset M, Francoual J, Beziaud L, Pallandre JR, Marie Joseph EL, Asgarova A, Borg C, Saati TA, Godet Y, Latouche JB, Valmary-Degano S, Adotévi O
Lien Pubmed
Résumé
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.
Mots clés
HLA transgenic mouse, PD-L1, T cells, cancer immunotherapy, sarcoma
Référence
Oncotarget. 2017 Apr;: