Heterogeneous Expression of ACE2, TMPRSS2, and FURIN at Single-Cell Resolution in Advanced Non-Small Cell Lung Cancer.

Considering the high susceptibility of patients with advanced non-small cell lung cancer (NSCLC) to COVID-19, we explored the susceptible cell types and potential routes of SARS-CoV-2 infection in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) by analyzing the expression patterns of the entry receptor angiotensin converting enzyme 2 (ACE2) and the spike (S) protein priming proteases transmembrane serine protease 2 (TMPRSS2) and FURIN. Single-cell transcriptomic analysis of 14 LUSC and 12 LUAD samples was utilized to exhibit the heterogeneous expression of ACE2, TMPRSS2 and FURIN across different cell subsets and individuals. 12 cell types and 33 cell clusters were identified from 26 cancer samples. ACE2, TMPRSS2 and FURIN were heterogeneously expressed across different patients. Among all cell types, ACE2, TMPRSS2 and FURIN were predominately expressed in cancer cells and alveolar cells, and lowly uncovered in other cells. Compared to LUSC, the protein priming proteases (TMPRSS2 and FURIN) were highly found in LUAD samples. However, ACE2 was not differentially expressed in cancer cells between the two cancer types. Moreover, ACE2, TMPRSS2, and FURIN expressions were not higher in any cell type of smokers than non-smokers. Our research first revealed the heterogeneous expression of ACE2, TMPRSS2, and FURIN in different cell subsets of NSCLC and also across different individuals. These results provide insight into the specific cells targeted by SARS-CoV-2 (i.e., cancer cells and alveolar cells) in patients with advanced NSCLC, and indicate that smoking may be not an independent risk factor for NSCLC combined with COVID-19.