title: Anti-PD-L1 treatment enhances antitumor effect of everolimus in a mouse model of renal cell carcinoma.
abstract: Immunotherapy based on blockade of the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has shown promising clinical activity for renal cell carcinoma (RCC) patients; however, the most effective use of these agents in combination with conventional targeted therapy remains to be resolved. Here we evaluated the therapeutic efficacy of the combination of the mTOR inhibitor everolimus (EVE) and anti-PD-L1 using an immunocompetent mouse model of RCC. We first assessed the in vitro effect of EVE on PD-L1 expression in the human 786-O and mouse RENCA RCC cell lines and found that EVE upregulated PD-L1 expression in these RCC cell lines. We then treated RENCA tumor-bearing mice with EVE and found that PD-L1 expression was also increased in tumor cells after EVE treatment. To determine the antitumor effects of EVE alone, anti-PD-L1 alone, and EVE in combination with anti-PD-L1, we evaluated their antitumor effects on RENCA tumor-bearing mice. A significant decrease in the tumor burden was observed in the EVE alone but not in the anti-PD-L1 alone treatment group compared with the control group. Importantly, the combination of EVE with anti-PD-L1 significantly reduced tumor burden compared with the EVE alone treatment, increasing tumor infiltrating lymphocytes (TILs) and the ratio of cytotoxic CD8+T cells to TILs. The results of the present study demonstrated that anti-PD-L1 treatment enhanced the antitumor effect of EVE in a mouse model, supporting a direct translation of this combination strategy to the clinic for the treatment of RCC.
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.|Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yukiyoshi
authors.initials: Y
authors.lastname: Hirayama
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Min
authors.initials: M
authors.lastname: Gi
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Yamano
authors.affiliation: Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tachibana
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tamada
authors.affiliation: Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nakatani
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015415:Biomarkers; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D000068338:Everolimus / Q000494:pharmacology*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; D015415:Biomarkers; D000068338:Everolimus
keywords: Everolimus; PD-1; PD-L1; immune checkpoint; renal cell carcinoma