Epithelial-to-mesenchymal transition promotes immune escape by inducing CD70 in non-small cell lung cancer. (July 2022)

• Record Type: Journal Article
• Authors: Ortiz-Cuaran, Sandra; Swalduz, Aurélie; Foy, Jean-Philippe; Marteau, Solène; Morel, Anne-Pierre; Fauvet, Frédérique; De Souza, Geneviève; Michon, Lucas; Boussageon, Maxime; Gadot, Nicolas; Godefroy, Marion; Léon, Sophie; Tortereau, Antonin; Mourksi, Nour-El-Houda; Leonce, Camille; Albaret, Marie Alexandra; Dongre, Anushka; Vanbervliet, Béatrice; Robert, Marie; Tonon, Laurie; Pommier, Roxane M.; Hofman, Véronique; Attignon, Valéry; Boyault, Sandrine; Audoynaud, Carole; Auclair, Jessie; Bouquet, Fanny; Wang, Qing; Ménétrier-Caux, Christine; Pérol, Maurice; Caux, Christophe; Hofman, Paul; Lantuejoul, Sylvie; Puisieux, Alain; Saintigny, Pierre;
• Is Part Of: European journal of cancer. Volume 169(2022)
• Page Start: 106
• Page End: 122
• Publication Date: 2022-07
• Subjects: CD70 -- Lung cancer -- Epithelial-to-mesenchymal transition -- Sarcomatoid carcinomas; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2022.03.038
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Introduction: Epithelial-to-mesenchymal transition (EMT) is associated with tumor aggressiveness, drug resistance, and poor survival in non-small cell lung cancer (NSCLC) and other cancers. The identification of immune-checkpoint ligands (ICPLs) associated with NSCLCs that display a mesenchymal phenotype (mNSCLC) could help to define subgroups of patients who may benefit from treatment strategies using immunotherapy. Methods: We evaluated ICPL expression in silico in 130 NSCLC cell lines. In vitro, CRISPR/Cas9-mediated knockdown and lentiviral expression were used to assess the impact of ZEB1 expression on CD70. Gene expression profiles of lung cancer samples from the TCGA (n = 1018) and a dataset from MD Anderson Cancer Center (n = 275) were analyzed. Independent validation was performed by immunohistochemistry and targeted-RNA sequencing in 154 NSCLC whole sections, including a large cohort of pulmonary sarcomatoid carcinomas (SC, n = 55). Results: We uncover that the expression of CD70, a regulatory ligand from the tumor necrosis factor ligand family, is enriched in mNSCLC in vitro models. Mechanistically, the EMT-inducer ZEB1 impacted CD70 expression and fostered increased activity of the CD70 promoter. CD70 overexpression was also evidenced in mNSCLC patient tumor samples and was particularly enriched in SC, a lung cancer subtype associated with poor prognosis. In these tumors, CD70 expression was associated with decreased CD3 + and CD8 + T-cell infiltration and increased T-cell exhaustion markers. Conclusion: Our results provide evidence on the pivotal roles of CD70 and ZEB1 in immune escape in mNSCLC, suggesting that EMT might promote cancer progression and metastasis by not only increasing cancer cell plasticity but also reprogramming the immune response in the local tumor microenvironment. Highlights: The EMT-inducer ZEB1 modulates the expression of CD70, a ligand from the TNF family. CD70 expression is enriched in pulmonary sarcomatoid carcinomas (SC). In SC, CD70 expression is associated with features of an immunosuppressive environment.