TY - JOUR
T1 - Comorbidity between lung cancer and COVID-19 pneumonia
T2 - role of immunoregulatory gene transcripts in high ACE2-expressing normal lung
AU - Lazar, Vladimir
AU - Raynaud, Jacques
AU - Magidi, Shai
AU - Bresson, Catherine
AU - Martini, Jean François
AU - Galbraith, Susan
AU - Wunder, Fanny
AU - Onn, Amir
AU - Batist, Gerald
AU - Girard, Nicolas
AU - Lassen, Ulrik
AU - Pramesh, C. S.
AU - Al-Omari, Amal
AU - Ikeda, Sadakatsu
AU - Berchem, Guy
AU - Blay, Jean Yves
AU - Solomon, Benjamin
AU - Felip, Enriqueta
AU - Tabernero, Josep
AU - Rubin, Eitan
AU - Philip, Thierry
AU - Porgador, Angel
AU - Berindan-Neagoe, Ioana
AU - Schilsky, Richard L.
AU - Kurzrock, Razelle
N1 - Funding Information:
• Dr Enriqueta Felip receives advisory board and/or speaker’s bureau fee from AbbVie, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GSK, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, PeerVoice, Pfizer, priME Oncology, Puma Biotechnology, Sanofi Genzyme, Springer, Takeda, touchIME; on the board of Grifols, Independent member. Receives research funding from Fundación Merck Salud, Grant for Oncology Innovation EMD Serono.
Funding Information:
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The research leading to these results on the CHEMORES study data, an initiative from the Chemotherapy resistance consortium, has received funding from the European Union Sixth Framework (FP6) Integrated Project. The research on the WINTHER trial data leading to these results has received funding from the European Union Seventh Framework Program (FP7) (WINTHER: FP7/2007-2013 under grant agreement n°306125). WINTHER, an initiative from the WIN Consortium, was funded in part by ARC Foundation for cancer research (France), Pfizer Oncology, Lilly France SAS, and Novartis Pharmaceuticals Corporation. Funded in part by The FERO/J.P. Morgan Private Bank Clinical Oncology Research Grant, National Cancer Institute grant P30 P30-CA023100 (RK), Israeli Science Foundation grant 1188/16 (ER), Instituto Salud Carlos III – Programa Rio Hortega Contract grant CM15/00255 (EF) and Canadian Institutes for Health Research (grant MOP-142281, GB) and the Canadian Cancer Society (grant 703811, GB).
Publisher Copyright:
© The Author(s), 2022.
PY - 2022/10/28
Y1 - 2022/10/28
N2 - 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.
AB - 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.
KW - ACE2 expression
KW - cancer
KW - COVID-19
KW - normal lung
KW - transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85141422808&partnerID=8YFLogxK
U2 - 10.1177/17588359221133893
DO - 10.1177/17588359221133893
M3 - Article
C2 - 36324736
VL - 14
JO - Therapeutic Advances in Medical Oncology
JF - Therapeutic Advances in Medical Oncology
SN - 1758-8340
ER -