TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients

Andrea Sacconi,Francesca Spinella,Stefano Ferrero,Giuseppe Sanguineti,Gennaro Ciliberto,Nishant Agrawal,Sabrina Strano,Evgeny Izumchenko,Fulvia Pimpinelli,Fabrizio Ensoli,Sara Donzelli,Claudio Pulito,Marta Rigoni,Aldo Giannì,Raul Pellini,Giovanni Blandino,Paola Muti,Aldo Morrone

doi:10.1186/s13046-020-01708-6

Abstract

BackgroundSARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. We aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity, pharynx, larynx and lung tissues as well as neoplastic tissues from the same areas.MethodsThe study has been conducted using the TCGA and the Regina Elena Institute databases and validated by experimental model in HNSCC cells. We also included data from one COVID19 patient who went under surgery for HNSCC.ResultsTMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues. It was more evident in women than in men, in TP53 mutated versus wild TP53 tumors, in HPV negative patients compared to HPV positive counterparts. Functionally, we modeled the multivariate effect of TP53, HPV, and other inherent variables on TMPRSS2. All variables had a statistically significant independent effect on TMPRSS2. In particular, in tumor tissues, HPV negative, TP53 mutated status and elevated TP53-dependent Myc-target genes were associated with low TMPRSS2 expression. The further analysis of both TCGA and our institutional HNSCC datasets identified a signature anti-correlated to TMPRSS2. As proof-of-principle we also validated the anti-correlation between microRNAs and TMPRSS2 expression in a SARS-CoV-2 positive HNSCC patient tissues Finally, we did not find TMPRSS2 promoter methylation.ConclusionsCollectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.

Highlights

SARS-coronavirus-2 enters host cells through binding of the Spike protein to Angiotensin I Converting Enzyme 2 (ACE2) receptor and subsequent S priming by the TMPRSS2 protease
We found that unlike ACE2, whose expression was unchanged in head and neck squamous cell carcinoma (HNSCC) patients, Transmembrane Serine Protease 2 (TPMRSS2) expression was significantly reduced in tumor tissues compared to non-tumorous ones in both HNSCC The Cancer Genome Atlas (TCGA) and Regina Elena Institute (IRE) datasets
ACE2 and TMPRSS2 expression in HNSCC patients To test our hypothesis, we first assessed the expression of both ACE2 and TMPRSS2 in TCGA HNSCC dataset

Summary

Introduction

SARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. SARS-CoV-2 enters host cells through the binding of Spike protein to ACE2 receptor and subsequent S protein priming performed by host proteases including TPMRSS2 [6,7,8]. In the past two decades new surgical and medical treatments have improved patients’ quality of life, the 5-year survival remains 40–50% of patients [11]. Advances in treatments for HNSCC over the past two decades failed to substantially improve the overall disease outcome, with radio and chemoresistance (intrinsic or acquired) remains one of the major challenges in the current therapy of HNSCC

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