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

Vladimir Lazar, Jacques Raynaud, Shai Magidi, Catherine Bresson, Jean François Martini, Susan Galbraith, Fanny Wunder, Amir Onn, Gerald Batist, Nicolas Girard, Ulrik Lassen, C. S. Pramesh, Amal Al-Omari, Sadakatsu Ikeda, Guy Berchem, Jean Yves Blay, Benjamin Solomon, Enriqueta Felip, Josep Tabernero, Eitan RubinThierry Philip, Angel Porgador, Ioana Berindan-Neagoe, Richard L. Schilsky, Razelle Kurzrock

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Number of pages15
JournalTherapeutic Advances in Medical Oncology
Volume14
DOIs
StatePublished - 28 Oct 2022

Keywords

  • ACE2 expression
  • cancer
  • COVID-19
  • normal lung
  • transcriptomics

ASJC Scopus subject areas

  • Oncology

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