Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti-PD-1+Antiangiogenesis in Malignant Pleural Mesothelioma

被引：12

作者：

Danlos, Francois-Xavier ^{[1
,2
,3
,4
]}

Texier, Matthieu ^{[5
]}

Job, Bastien ^{[6
]}

Mouraud, Severine ^{[2
,3
]}

Cassard, Lydie ^{[7
,8
]}

Baldini, Capucine ^{[1
]}

Varga, Andrea ^{[1
]}

Yurchenko, Andrey A. ^{[9
]}

Rabeau, Audrey ^{[10
]}

Champiat, Stephane ^{[1
,2
,3
]}

Letourneur, Diane ^{[2
,3
,11
]}

Bredel, Delphine ^{[2
,3
]}

Susini, Sandrine ^{[2
,3
]}

Blum, Yuna ^{[12
]}

Parpaleix, Aurelien ^{[13
]}

Parlavecchio, Cedric ^{[13
]}

Tselikas, Lambros ^{[2
,3
,4
,14
]}

Fahrner, Jean-Eudes ^{[2
,3
]}

Goubet, Anne-Gaelle ^{[2
,3
,4
]}

Rouanne, Mathieu ^{[2
,3
,4
]}

Rafie, Saloomeh ^{[1
]}

Abbassi, Alae ^{[1
]}

Kasraoui, Ines ^{[15
]}

Breckler, Marie ^{[16
]}

Farhane, Siham ^{[1
]}

Ammari, Samy ^{[15
]}

Laghouati, Salim ^{[17
]}

Gazzah, Anas ^{[1
]}

Lacroix, Ludovic ^{[18
,19
]}

Besse, Benjamin ^{[20
]}

Droin, Nathalie ^{[16
]}

Deloger, Marc ^{[6
]}

Cotteret, Sophie ^{[21
]}

Adam, Julien ^{[22
]}

Zitvogel, Laurence ^{[2
,3
,4
]}

Nikolaev, Sergey I. ^{[9
]}

Chaput, Nathalie ^{[7
,8
,23
]}

Massard, Christophe ^{[1
]}

Soria, Jean-Charles ^{[24
]}

Gomez-Roca, Carlos ^{[10
]}

Zalcman, Gerard ^{[25
]}

Planchard, David ^{[20
]}

Marabelle, Aurelien ^{[1
,2
,3
,4
]}

机构：

[1] Gustave Roussy, DITEP, Villejuif, France

[2] Gustave Roussy, INSERM U1015, Villejuif, France

[3] Gustave Roussy, CIC1428 BIOTHERIS, Villejuif, France

[4] Univ Paris Saclay, Fac Med, Le Kremlin Bicetre, France

[5] Univ Paris Saclay, Serv Biostat & Epidemiol, Oncostat INSERM U1018, Gustave Roussy, Villejuif, France

[6] Univ Paris Saclay, CNRS UMS 3655, Plateforme Bioinformat, INSERM US23,Gustave Roussy, Villejuif, France

[7] Gustave Roussy, CNRS UMS 3655, LIO, Villejuif, France

[8] Gustave Roussy, INSERM US23, Villejuif, France

[9] Univ Paris Saclay, INSERM U981, Gustave Roussy, Villejuif, France

[10] Inst Univ Canc Toulouse, Inst Claudius Regaud, Dept Med Oncol, Toulouse, France

[11] Univ Claude Bernard Lyon I, Univ Lyon, Ecole Normale Super Lyon, Lyon, France

[12] Univ Rennes, UMR6290, IGDR, INSERM,ERL U1305,INSERM,CNRS, Rennes, France

[13] Gustave Roussy, Equipe Promot, BPP, DRC, Villejuif, France

[14] Gustave Roussy, DACII, Villejuif, France

[15] Univ Paris Saclay, CNRS, Dept Radiol, Biomaps,UMR1281,INSERM,CEA,Gustave Roussy, Villejuif, France

[16] CNRS UAR 3655, Gustave Roussy Canc Ctr, INSERM US23, AMMICa,Genom Platform, Villejuif, France

[17] Gustave Roussy, Unite Fonct Pharmacovigilance, Villejuif, France

[18] CNRS UMS 3655, Dept Biol & Pathol Med, Plateforme Biopathol Mol, Villejuif, France

[19] INSERM, US23, Villejuif, France

[20] Gustave Roussy, Dept Med Oncol, Villejuif, France

[21] Gustave Roussy, Lab Cytogenet, Villejuif, France

[22] Gustave Roussy, INSERM U1186, Villejuif, France

[23] Univ Paris Saclay, Fac Pharm, Orsay, France

[24] Amgen Inc, Thousand Oaks, CA USA

[25] Univ Paris, Serv Pneumol, Hop Bichat, APHP, Paris, France

来源：

CANCER DISCOVERY | 2023年 / 13卷 / 04期

基金：

欧盟地平线“2020”;

关键词：

ENDOTHELIAL GROWTH-FACTOR; OPEN-LABEL; T-CELLS; QUANTIFICATION; MULTICENTER; BEVACIZUMAB; EXPRESSION; CISPLATIN; ASBESTOS; BIOLOGY;

D O I：

10.1158/2159-8290.CD-22-0886

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas' primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti-PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.

引用

页码：858 / 879

页数：22

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