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

V. Lazar*, J. Raynaud, S. Magidi, C. Bresson, J. F. Martini, S. Galbraith, F. Wunder, A. Onn, G. Batist, N. Girard, U. Lassen, C. S. Pramesh, A. Al-Omari, S. Ikeda, G. Berchem, J. Y. Blay, B. Solomon, E. Felip, J. Tabernero, E. RubinT. Philip, A. Porgador, I. Berindan-Neagoe, R. L. Schilsky, R. Kurzrock

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)


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.

Original languageEnglish
Article number17588359221133893
JournalTherapeutic Advances in Medical Oncology
Publication statusPublished - 28 Oct 2022


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