In silico prediction of COVID-19 cytokine storm in lung cancer types

Abstract

Lung cancer is one of the most frequently diagnosed malignant tumors and the leading cause of cancer-related death worldwide. Mainly, Non-small-cell lung cancer (NSCLC), which accounts for more than eighty-five percent of all lung cancers, consists of two major subtypes: lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). Novel coronavirus disease (COVID-19) affected millions of people caused by acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) around the globe. Lung cancer patients and COVID-19 present unique and unfortunate lethal combinations because the lungs are the primary target organ of SARS-CoV-2 infection. Clinical studies have demonstrated that an over-activated inflammatory response associated with severe COVID-19 cases is characterized by excessive auto-amplifying cytokine release, which is defined as a "cytokine storm." ACE2 and TMPRSS2 receptors play an essential role in SARS-CoV-2 infection; therefore, using in silico analysis, we did correlation analysis with immune infiltration markers in LUAD and LUSC patient groups. Our study identified a promising correlation between immune-modulators and receptor proteins (ACE-2 and TMPRSS2), creating a domain that requires further laboratory studies for clinical authentication.

Keywords: ACE-2; COVID-19; Cytokine storm; Immune-modulators; Lung cancer; TMPRSS2.

Fig. 1

The distribution of ACE2 and TMPRSS2 mRNA expression trends in lung tissues: (A) the distribution of ACE2 mRNA expression in LUAD and LUSC between tumor tissue represented in red and normal tissues represented in green; (B) correlation between ACE2 expression level trends in different LUAD pathological stages; (C) correlation between ACE2 expression level trends in different LUSC pathological stages; (D) the distribution of TMPRSS2 mRNA expression in LUAD and LUSC between tumor tissue represented in red and normal tissues represented in green; (E) Correlation between TMPRSS2 expression level trends in different LUAD pathological stages; (F) Correlation between TMPRSSS22 expression level trends in different LUSC pathological stages Abbreviations: LUSC, lung squamous cell carcinoma; LUAD, lung adenocarcinoma; GEPIA, gene expression profiling interactive analysis; T, tumor; N, normal control. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Correlation between ACE2 and TMPRSS2 expression and lymphocytes. The pan-cancer analysis of relationship between abundance of the 28 tumor-infiltrating lymphocytes (TILs) and (A) ACE2 and (B) TMPRSS2 expression.

Fig. 3

Correlation analysis between ACE2 and TMPRSS2 with immune infiltration level. Heatmap clustering analysis performed in MetaboAnalyst 4.0 showed the spearman correlation-based analysis with the level of significance of immune-modulators with ACE2 and TMPRSS2 expression in LUAD and LUSC using TIMER analysis. MetaboAnalyst 4.0 was used for generating the Heat map (https://www.metaboanalyst.ca/MetaboAnalyst/ModuleView.xhtml). Colored bars represent differential levels of Spearman's correlation. Blue represents negative correlation values while the red represents the positive correlation values. TIMER web tool (https://cistrome.shinyapps.io/timer/) was used for statistically analyzing the correlation values. The statistical significance is annotated by the number of stars (*: P-value < 0.05; **: P-value <0.01; ***: P-value <0.001; ****: P-value <0.0001). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

- Three steps predictive model of SARS-CoV-2 consortium with lung cancer types: The predictive implications towards the ACE2 inhibitors in lung cancer types has been shown in three major steps i) Infection: As high expression of ACE2 in LUAD leads to increase in virus susceptibility compared to LUSC. ii) Receptor internalization: A major step in immunomodulation and provoking cytokine storm due to negative correlation of ACE2 with immune modulators in LUAD. iii) Call for cytokine storm/Resolution: Hyper-inflammatory response in LUAD while it diminishes the immune response in LUSC.