Comorbidity between lung cancer and COVID-19 pneumonia: role of immunoregulatory gene transcripts in high ACE2-expressing normal lung. (October 2022)

• Record Type: Journal Article
• Authors: Lazar, Vladimir; Raynaud, Jacques; Magidi, Shai; Bresson, Catherine; Martini, Jean-François; Galbraith, Susan; Wunder, Fanny; Onn, Amir; Batist, Gerald; Girard, Nicolas; Lassen, Ulrik; Pramesh, C. S.; Al-Omari, Amal; Ikeda, Sadakatsu; Berchem, Guy; Blay, Jean-Yves; Solomon, Benjamin; Felip, Enriqueta; Tabernero, Josep; Rubin, Eitan; Philip, Thierry; Porgador, Angel; Berindan-Neagoe, Ioana; Schilsky, Richard L.; Kurzrock, Razelle
• Is Part Of: Therapeutic advances in medical oncology. Volume 14(2022)
• Publication Date: 2022-10
• Subjects: ACE2 expression -- cancer -- COVID-19 -- normal lung -- transcriptomics; Oncology -- Periodicals; Cancer -- Treatment -- Periodicals; 616.994005
• DOI: 10.1177/17588359221133893
• Languages: English
• ISSNs: 1758-8340

Abstract

Background: SARS-CoV-2 (COVID-19) elicits a T-cell antigen-mediated immune response of variable efficacy. To understand this variability, we explored transcriptomic expression of angiotensin-converting enzyme 2 ( ACE2, the SARS-CoV-2 receptor) and of immunoregulatory genes in normal lung tissues from patients with non-small cell lung cancer (NSCLC). Methods: This study used the transcriptomic and the clinical data for NSCLC patients generated during the CHEMORES study [ n = 123 primary resected (early-stage) NSCLC] and the WINTHER clinical trial ( n = 32 metastatic NSCLC). Results: We identified patient subgroups with high and low ACE2 expression ( p = 1.55 × 10 −19 ) in normal lung tissue, presumed to be at higher and lower risk, respectively, of developing severe COVID-19 should they become infected. ACE2 transcript expression in normal lung tissues (but not in tumor tissue) of patients with NSCLC was higher in individuals with more advanced disease. High- ACE2 expressors had significantly higher levels of CD8+ cytotoxic T lymphocytes and natural killer cells but with presumably impaired function by high Thymocyte Selection-Associated High Mobility Group Box Protein TOX ( TOX ) expression. In addition, immune checkpoint-related molecules – PD-L1, CTLA-4, PD-1, and TIGIT – are more highly expressed in normal (but not tumor) lung tissues; these molecules might dampen immune response to either viruses or cancer. Importantly, however, high inducible T-cell co-stimulator ( ICOS ), which can amplify immune and cytokine reactivity, significantly correlated with high ACE2 expression in univariable analysis of normal lung (but not lung tumor tissue). Conclusions: We report a normal lung immune-tolerant state that may explain a potential comorbidity risk between two diseases – NSCLC and susceptibility to COVID-19 pneumonia. Further, a NSCLC patient subgroup has normal lung tissue expressing high ACE2 and high ICOS transcripts, the latter potentially promoting a hyperimmune response, and possibly leading to severe COVID-19 pulmonary compromise.