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

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.

• Authors: 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, Olivier Adotévi
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 30 Pg. 48959-48971 (07 25 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28430664 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• B7-H1 Antigen
• CD274 protein, human
• HLA-A*02:01 antigen
• HLA-A2 Antigen
• HLA-DRB1 Chains

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics, immunology)
• B7-H1 Antigen (genetics, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Disease Models, Animal
• Female
• Gene Expression
• Gene Expression Profiling
• HLA-A2 Antigen (genetics, immunology)
• HLA-DRB1 Chains (genetics, immunology)
• Humans
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology, metabolism)
• Male
• Mice
• Mice, Transgenic
• Neoplasms (genetics, immunology, metabolism, pathology)
• Sarcoma (genetics, metabolism, pathology)