Anti-PD-L1 treatment enhances antitumor effect of everolimus in a mouse model of renal cell carcinoma.
Anti-PD-L1 treatment enhances antitumor effect of everolimus in a mouse model of renal cell carcinoma.
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DOI：
10.1111/cas.13099
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发表时间：
2016-12
期刊：
影响因子：
5.7
通讯作者：
Wanibuchi H
中科院分区：
文献类型：
--
作者：
Hirayama Y;Gi M;Yamano S;Tachibana H;Okuno T;Tamada S;Nakatani T;Wanibuchi H
基于阻断程序性死亡-1（PD-1）/程序性死亡配体1（PD-L1）轴的免疫治疗已显示出对肾细胞癌（RCC）患者有前景的临床活性;然而，这些药物与常规靶向治疗联合使用的最有效方法仍有待解决。在这里，我们使用RCC的免疫活性小鼠模型评估了mTOR抑制剂依维莫司（EVE）和抗PD-L1的组合的治疗功效。我们首先评估了EVE对人786-O和小鼠RENCA RCC细胞系中PD-L1表达的体外作用，发现EVE上调了这些RCC细胞系中的PD-L1表达。然后，我们用EVE治疗RENCA荷瘤小鼠，发现EVE治疗后肿瘤细胞中的PD-L1表达也增加。为了确定EVE单独、抗PD-L1单独和EVE与抗PD-L1联合的抗肿瘤作用，我们评价了它们对RENCA荷瘤小鼠的抗肿瘤作用。与对照组相比，在EVE单药治疗组中观察到肿瘤负荷显著降低，但在抗PD-L1单药治疗组中未观察到。重要的是，与EVE单独治疗相比，EVE与抗PD-L1联合治疗显著降低了肿瘤负荷，增加了肿瘤浸润淋巴细胞（TIL）和细胞毒性CD 8 + T细胞与TIL的比例。本研究的结果表明，抗PD-L1治疗增强了EVE在小鼠模型中的抗肿瘤作用，支持将这种联合策略直接转化为临床治疗RCC。
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.
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DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
3.5
作者：
Lee, SJ;Jang, BC;Choi, IH
通讯作者：
Choi, IH
影响因子：
--
作者：
Harter PN;Bernatz S;Scholz A;Zeiner PS;Zinke J;Kiyose M;Blasel S;Beschorner R;Senft C;Bender B;Ronellenfitsch MW;Wikman H;Glatzel M;Meinhardt M;Juratli TA;Steinbach JP;Plate KH;Wischhusen J;Weide B;Mittelbronn M
通讯作者：
Mittelbronn M
DOI：
10.1056/nejmoa1510665
发表时间：
2015-11-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Motzer RJ;Escudier B;McDermott DF;George S;Hammers HJ;Srinivas S;Tykodi SS;Sosman JA;Procopio G;Plimack ER;Castellano D;Choueiri TK;Gurney H;Donskov F;Bono P;Wagstaff J;Gauler TC;Ueda T;Tomita Y;Schutz FA;Kollmannsberger C;Larkin J;Ravaud A;Simon JS;Xu LA;Waxman IM;Sharma P;CheckMate 025 Investigators
通讯作者：
CheckMate 025 Investigators
DOI：
10.1158/1078-0432.ccr-15-2839
发表时间：
2016-11-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Choueiri TK;Fishman MN;Escudier B;McDermott DF;Drake CG;Kluger H;Stadler WM;Perez-Gracia JL;McNeel DG;Curti B;Harrison MR;Plimack ER;Appleman L;Fong L;Albiges L;Cohen L;Young TC;Chasalow SD;Ross-Macdonald P;Srivastava S;Jure-Kunkel M;Kurland JF;Simon JS;Sznol M
通讯作者：
Sznol M