Identification of unique immune response expression profiles to SARS-CoV-2 in non-small cell lung cancer using systems immunology approach

Background: COVID-19 severity and mortality are higher in patients with lung cancer due to pulmonary complications. Understanding the mechanisms of SARS-COV-2 effect on lung cancer cells in comparison to healthy lung cells can improve our knowledge of the disease biology to discover new therapeutic targets with the aim of improving the management protocols. Methods: We aimed to investigate the immune response signature generated from COVID-19-infected NSCLC patients and compare with noninfected patients. To achieve this, publicly available transcriptomic data of lung adenocarcinoma cancer cells A549 versus healthy lung epithelium which were SARS-COV-2-infected and mock-infected were retrieved and reanalyzed to identify differentially expressed genes (DEGs) that are dysregulated in SARS-COV-2-infected A549. Identified genes were explored for enriched pathways and further validated in silico for their expression in larger NSCLC lung samples. C57BL/6J mice infected with MA15 (mouse-adapted SARS-CoV) were used to confirm the findings. Results: A total of 7852 DEGs were identified between A549 (mock and SARS-COV-2 infected) compared to healthy epithelial cells (mock and SARS-COV-2 infected). On the contrary, 142 genes were DEGs between all mocked-infected cells (healthy and cancer) versus SARS-COV-2 infected (healthy and cancer). Those 142 genes were intersected with DEGs from the first step and were shown to be involved in cytokine-mediated signaling pathway and lymphocyte activation. A549-infected cells upregulated (IL11, RBCK1, CEBPD, EBI3, and ISG15) to a higher proportion but downregulated RELB compared to the healthy epithelium. Most of the genes (Nr1h4, Ebi3, Snai2, IL2rb, IL11, Clec4e, Cebpd, and Relb) were differentially expressed in the lung of infected mice. In silico validation confirm that IL11 expression is higher in lung adenocarcinoma compared to healthy controls. COVID-19 infection in NSCLC patients lead to the activation of specific cytokines. Conclusions: Our analysis showed IL11 to be the most differentially expressed between cancer and non-cancer patients and was associated with poor prognosis suggesting that COVID-19 infection in cancer patients leads to the synergistic increase in expression of CD4+ T cells, M1 macrophages, and follicular helper T cells.