Anti-PD-L1 treatment enhances antitumor effect of everolimus in a mouse model of renal cell carcinoma

作者：Hirayama Yukiyoshi; Gi Min; Yamano Shotaro; Tachibana Hirokazu; Okuno Takahiro; Tamada Satoshi; Nakatani Tatsuya; Wanibuchi Hideki

来源：CANCER SCIENCE, 2016, 107(12): 1736-1744.

DOI：10.1111/cas.13099

<jats:p>Immunotherapy based on blockade of the programmed death‐1 (<jats:styled-content style="fixed-case">PD</jats:styled-content>‐1)/programmed death‐ligand 1 (<jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1) axis has shown promising clinical activity for renal cell carcinoma (<jats:styled-content style="fixed-case">RCC</jats:styled-content>) 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 <jats:styled-content style="fixed-case">mTOR</jats:styled-content> inhibitor everolimus (<jats:styled-content style="fixed-case">EVE</jats:styled-content>) and anti‐<jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1 using an immunocompetent mouse model of <jats:styled-content style="fixed-case">RCC</jats:styled-content>. We first assessed the <jats:italic>in vitro</jats:italic> effect of <jats:styled-content style="fixed-case">EVE</jats:styled-content> on <jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1 expression in the human 786‐O and mouse <jats:styled-content style="fixed-case">RENCA RCC</jats:styled-content> cell lines and found that <jats:styled-content style="fixed-case">EVE</jats:styled-content> upregulated <jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1 expression in these <jats:styled-content style="fixed-case">RCC</jats:styled-content> cell lines. We then treated <jats:styled-content style="fixed-case">RENCA</jats:styled-content> tumor‐bearing mice with <jats:styled-content style="fixed-case">EVE</jats:styled-content> and found that <jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1 expression was also increased in tumor cells after <jats:styled-content style="fixed-case">EVE</jats:styled-content> treatment. To determine the antitumor effects of <jats:styled-content style="fixed-case">EVE</jats:styled-content> alone, anti‐<jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1 alone, and <jats:styled-content style="fixed-case">EVE</jats:styled-content> in combination with anti‐<jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1, we evaluated their antitumor effects on <jats:styled-content style="fixed-case">RENCA</jats:styled-content> tumor‐bearing mice. A significant decrease in the tumor burden was observed in the <jats:styled-content style="fixed-case">EVE</jats:styled-content> alone but not in the anti‐<jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1 alone treatment group compared with the control group. Importantly, the combination of <jats:styled-content style="fixed-case">EVE</jats:styled-content> with anti‐<jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1 significantly reduced tumor burden compared with the <jats:styled-content style="fixed-case">EVE</jats:styled-content> alone treatment, increasing tumor infiltrating lymphocytes (<jats:styled-content style="fixed-case">TIL</jats:styled-content>s) and the ratio of cytotoxic <jats:styled-content style="fixed-case">CD</jats:styled-content>8<jats:sup>+</jats:sup> T cells to <jats:styled-content style="fixed-case">TIL</jats:styled-content>s. The results of the present study demonstrated that anti‐<jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1 treatment enhanced the antitumor effect of <jats:styled-content style="fixed-case">EVE</jats:styled-content> in a mouse model, supporting a direct translation of this combination strategy to the clinic for the treatment of <jats:styled-content style="fixed-case">RCC</jats:styled-content>.</jats:p>

• 出版日期2016-12