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

• Published in: Therapeutic advances in medical oncology 2022, Vol.14, p.17588359221133893-17588359221133893
• Main 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
• Format: Article
• Language: English
• Subjects: ACE2; Angiotensin; Angiotensin-converting enzyme 2; CD8 antigen; Comorbidity; Coronaviruses; COVID-19; CTLA-4 protein; Cytotoxicity; High mobility group proteins; Immune checkpoint; Immune response; Immunoregulation; Lung cancer; Lymphocytes T; Metastases; Natural killer cells; Non-small cell lung carcinoma; Original Research; Patients; PD-1 protein; PD-L1 protein; Peptidyl-dipeptidase A; Pneumonia; Severe acute respiratory syndrome coronavirus 2; Small cell lung carcinoma; Transcriptomics; Tumors
• ISSN: 1758-8359; 1758-8340; 1758-8359
• DOI: 10.1177/17588359221133893

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.