TMPRSS2 Is a Tumor Suppressor and Its Downregulation Promotes Antitumor Immunity and Immunotherapy Response in Lung Adenocarcinoma

Authors

• Zhixian Liu
• Qiqi Lu
• Zhilan Zhang
• Qiushi Feng
• Xiaosheng Wang

Language

English

Publication Date

6-11-2024

Journal

Respiratory Research

DOI

10.1186/s12931-024-02870-7

PMID

38862975

PMCID

PMC11167788

PubMedCentral® Posted Date

6-11-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Background: TMPRSS2, a key molecule for SARS-CoV-2 invading human host cells, has an association with cancer. However, its association with lung cancer remains insufficiently unexplored.

Methods: In five bulk transcriptomics datasets, one single-cell RNA sequencing (scRNA-seq) dataset and one proteomics dataset for lung adenocarcinoma (LUAD), we explored associations between TMPRSS2 expression and immune signatures, tumor progression phenotypes, genomic features, and clinical prognosis in LUAD by the bioinformatics approach. Furthermore, we performed experimental validation of the bioinformatics findings.

Results: TMPRSS2 expression levels correlated negatively with the enrichment levels of both immune-stimulatory and immune-inhibitory signatures, while they correlated positively with the ratios of immune-stimulatory/immune-inhibitory signatures. It indicated that TMPRSS2 levels had a stronger negative correlation with immune-inhibitory than with immune-stimulatory signatures. TMPRSS2 downregulation correlated with increased proliferation, stemness, genomic instability, tumor progression, and worse survival in LUAD. We further validated that TMPRSS2 was downregulated with tumor progression in the LUAD cohort we collected from Jiangsu Cancer Hospital, China. In vitro and in vivo experiments verified the association of TMPRSS2 deficiency with increased tumor cell proliferation and invasion and antitumor immunity in LUAD. Moreover, in vivo experiments demonstrated that TMPRSS2-knockdown tumors were more sensitive to BMS-1, an inhibitor of PD-1/PD-L1.

Conclusions: TMPRSS2 is a tumor suppressor, while its downregulation is a positive biomarker of immunotherapy in LUAD. Our data provide a potential link between lung cancer and pneumonia caused by SARS-CoV-2 infection.

Keywords

Humans, Adenocarcinoma of Lung, Lung Neoplasms, Down-Regulation, Serine Endopeptidases, Animals, Mice, COVID-19, Immunotherapy, Gene Expression Regulation, Neoplastic, Male, Genes, Tumor Suppressor, Female, Mice, Nude, Cell Line, Tumor, SARS-CoV-2, Lung adenocarcinoma, SARS-CoV-2, TMPRSS2, Antitumor immune response, Tumor progression

Published Open-Access

yes

Recommended Citation

Liu, Zhixian; Lu, Qiqi; Zhang, Zhilan; et al., "TMPRSS2 Is a Tumor Suppressor and Its Downregulation Promotes Antitumor Immunity and Immunotherapy Response in Lung Adenocarcinoma" (2024). Faculty, Staff and Student Publications. 1006.
https://digitalcommons.library.tmc.edu/uthshis_docs/1006