Cisplatin increases PD-L1 expression and optimizes immune check-point blockade in non-small cell lung cancer

被引:184
作者
Fournel, Ludovic [1 ,2 ,3 ]
Wu, Zherui [2 ]
Stadler, Nicolas [2 ]
Damotte, Diane [4 ]
Lococo, Filippo [5 ]
Boulle, Geoffroy [4 ]
Segal-Bendirdjian, Evelyne [2 ]
Bobbio, Antonio [2 ,3 ]
Icard, Philippe [3 ,6 ]
Tredaniel, Jean [2 ,7 ]
Alifano, Marco [3 ]
Forgez, Patricia [2 ]
机构
[1] Paris Sud Saclay Univ, Ecole Doctorale Cancerol, Paris, France
[2] Paris Descartes Univ, Cellular Homeostasis & Canc Signaling, UMR 1124, INSERM, Paris, France
[3] Paris Descartes Univ, Paris Ctr Univ Hosp, Cochin Hosp, APHP,Thorac Surg Dept, Paris, France
[4] Paris Descartes Univ, Paris Ctr Univ Hosp, Cochin Hosp, APHP,Pathol Dept, Paris, France
[5] Arcispedale Santa Maria Nuova, Thorac Surg Dept, Azienda Unita Sanit Locale IRCCS Reggio Emilia, Reggio Emilia, Italy
[6] Caen Normandie Univ, BioTICLA Axis, Inserm U1086, F-14000 Caen, France
[7] Paris Descartes Univ, St Joseph Hosp, Resp Med & Thorac Oncol Dept, Paris, France
关键词
Immune check-point inhibitors; Cisplatin; PD-L1; Lung cancer; Neoadjuvant treatment; CHEMOTHERAPY; ACTIVATION; PATHWAY; TUMORS;
D O I
10.1016/j.canlet.2019.08.005
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The number of clinical protocols testing combined therapies including immune check-point inhibitors and platinum salts is currently increasing in lung cancer treatment, however preclinical studies and rationale are often lacking. Here, we evaluated the impact of cisplatin treatment on PD-L1 expression analyzing the clinicopathological characteristics of patients who received cisplatin-based neoadjuvant chemotherapy followed by surgery and showed that cisplatin-based induction treatment significantly increased PD-L1 staining in both tumor and immune cells from the microenvironment. Twenty-two patients exhibited positive PD-L1 staining variation after neoadjuvant chemotherapy; including 9 (23.1%) patients switching from < 50% to >= 50% of stained tumor-cells. We also confirmed the up-regulation of PD-L1 by cisplatin, at both RNA and protein levels, in nude and immunocompetent mice bearing tumors grafted with A549, LNM-R, or LLC1 lung cancer cell lines. The combined administration of anti-PD-L1 antibodies (3 mg/kg) and cisplatin (1 mg/kg) to mice harboring lung carcinoma significantly reduced tumor growth compared to single agent treatments and controls. Overall, these results suggest that cisplatin treatment could synergize with PD-1/PD-L1 blockade to increase the clinical response, in particular through early and sustainable enhancement of PD-L1 expression.
引用
收藏
页码:5 / 14
页数:10
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