Transmembrane serine protease 2, a SARS-CoV-2 internalization protease, correlates with clinical outcome, molecular features, and immunotherapy response in colorectal cancer

Chenjing Zhu; Jianfeng Wu; Vishal G Shelat; José María Sayagués; Seiichiro Yamamoto; Li Yang; Xia He

doi:10.21037/jgo-23-641

Transmembrane serine protease 2, a SARS-CoV-2 internalization protease, correlates with clinical outcome, molecular features, and immunotherapy response in colorectal cancer

J Gastrointest Oncol. 2023 Oct 31;14(5):2146-2157. doi: 10.21037/jgo-23-641. Epub 2023 Oct 24.

Authors

Chenjing Zhu^#¹, Jianfeng Wu^#¹, Vishal G Shelat², José María Sayagués³, Seiichiro Yamamoto⁴, Li Yang⁵, Xia He¹

Affiliations

¹ Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.
² Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore.
³ Pathology Service, Hospital Clínico Universitario de Salamanca and Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
⁴ Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan.
⁵ Endoscopy Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

^# Contributed equally.

Abstract

Background: Transmembrane serine protease 2 (TMPRSS2) mediates the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells. The relevant research indicates the intestine to be a target of SARS-CoV-2 infection, and thus we aimed to investigate the correlation between TMPRSS2 expression and the prognosis, molecular features, and immunotherapy response in patients with colorectal cancer (CRC).

Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used in this study and a total of 1,385 patients were identified. The CIBERSORT algorithms were used to evaluate the relative infiltration levels of immune cell types in the tumor microenvironment (TME). The correlation between TMPRSS2 expression and immunotherapy response rate was assessed in another 2 independent cohorts.

Results: TMPRSS2 expression was significantly downregulated in cancer tissue compared to the adjacent normal tissue, and patients with CRC with lower TMPRSS2 expression showed notably poorer prognosis. Functional enrichment analysis found that low TMPRSS2 expression was significantly associated with cancer metastasis-related pathways. Further analysis based on the miRWalk tool and JASPAR database identified a list of microRNAs (miRNAs) and transcriptional factors targeting TMPRSS2. Distinct differences in immune cell infiltration and tumor purity reflected by estimate and mutant-allele tumor heterogeneity score were observed between patients with low and high TMPRSS2 expression levels. Interestingly, patients with a low TMPRSS2 expression level showed a higher response rate to immunotherapy.

Conclusions: CRC cells may be more resistant to SARS-CoV-2 infection due to the decreased expression of TMPRSS2, which could be a newly identified biomarker for prognosis and immunotherapy response prediction in patients with CRC.

Keywords: Colorectal cancer (CRC); immunotherapy; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); transmembrane serine protease 2 (TMPRSS2); tumor microenvironment (TME).