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.
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.
Keywords
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Article info
Publication history
Published online: May 09, 2022
Accepted:
March 30,
2022
Received in revised form:
March 16,
2022
Received:
July 21,
2021
Identification
Copyright
© 2022 Elsevier Ltd. All rights reserved.
