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Severe Acute Respiratory Syndrome–Coronavirus-2 Infection and Patients With Lung Cancer: The Potential Role of Interleukin-17 Target Therapy

  • Stefano Cafarotti
    Correspondence
    Corresponding author. Address for correspondence: Stefano Cafarotti, MD, PD, UEMS, FEBTS, Clinical Director of Lung Unit OSG, Clinical Director of Lung Cancer Center IOSI (Istituto Oncologico della Svizzera Italiana) and Head of Thoracic Surgery, Department EOC (Ente Ospedaliero Cantonale), Università della Svizzera Italiana, Bellinzona 6500, Switzerland.
    Affiliations
    Istituto Oncologico della Svizzera Italiana, Università della Svizzera Italiana, Bellinzona, Switzerland
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Open AccessPublished:April 27, 2020DOI:https://doi.org/10.1016/j.jtho.2020.04.015

      Abstract

      The coronavirus disease 2019 outbreak is evolving rapidly worldwide. The lungs are the target of the primary infection and patients with lung cancer seem to have a poor prognosis. To our knowledge, this is the first reported investigation of a possible role of interleukin-17 target therapy in patients with lung cancer and concomitant severe acute respiratory syndrome–coronavirus-2 infection.

      Keywords

      Possible Role of interleukin-17 in Severe Acute Respiratory Syndrome–Coronavirus-2 Infection

      In the lungs, the interleukin-17 (IL-17) cytokine is produced by T helper-17 cells in response to viral infection.
      • Ryzhakov G.
      • Lai C.C.
      • Blazek K.
      • To K.W.
      • Hussell T.
      • Udalova I.
      IL-17 boosts proinflammatory outcome of antiviral response in human cells.
      IL-17 activates several signaling pathways, which in turn lead to the induction of chemokines. Chemokines recruit immune system cells to the inflammation site. The persistence of the pathogen generates hyperactivity of the immune system, which can lead to a cytokine storm.
      • Ryzhakov G.
      • Lai C.C.
      • Blazek K.
      • To K.W.
      • Hussell T.
      • Udalova I.
      IL-17 boosts proinflammatory outcome of antiviral response in human cells.
      Furthermore, IL-17, in synergy with IL-6, promotes viral persistence by inhibiting apoptosis.
      • Hou W.
      • Jin Y.H.
      • Kang H.S.
      • Kim B.S.
      Interleukin-6 (IL-6) and IL-17 synergistically promote viral persistence by inhibiting cellular apoptosis and cytotoxic T cell function.
      As per the same study, it is possible to determine the biologic mechanisms related to organ damage mediated by viruses through the IL-17 pathway.
      • Hou W.
      • Jin Y.H.
      • Kang H.S.
      • Kim B.S.
      Interleukin-6 (IL-6) and IL-17 synergistically promote viral persistence by inhibiting cellular apoptosis and cytotoxic T cell function.
      The role of IL-17 does not seem to be confined to these mechanisms. In fact, in addition to mediating the cytokine storm (resulting in lung damage) and inhibiting the apoptosis of infected cells (resulting in viral persistence), it also seems to have the ability to increase the replication of some viruses by actually increasing their virulence.
      • Patera A.C.
      • Pesnicak L.
      • Bertin J.
      • Cohen J.I.
      Interleukin 17 modulates the immune response to vaccinia virus infection.
      It has also been found in an experimental model that viral persistence, caused by generating a continuous increase in IL-17, produces acute respiratory distress syndrome,
      • Li J.T.
      • Melton A.C.
      • Su G.
      • et al.
      Unexpected role for adaptive αβTh17 cells in acute respiratory distress syndrome.
      which is what happens in severe acute respiratory syndrome–coronavirus-2 (SARS–CoV-2) infection. The increasing level of IL-17 could also be related to the hypercoagulation status in patients with coronavirus disease 2019 (COVID-19).
      • Ding P.
      • Zhang S.
      • Yu M.
      • et al.
      IL-17A promotes the formation of deep vein thrombosis in a mouse model.

      Adverse Outcome of COVID-19 Related to Previous Comorbidity

      On investigation of the risk factors related to the poor prognosis of COVID-19, it was revealed that the IL-17 pathway was always altered in these cases. In fact, with advancing age, inflammatory response to viruses is altered with an excessive increase in the production of IL-17.
      • Stout-Delgado H.W.
      • Du W.
      • Shirali A.C.
      • Booth C.J.
      • Goldstein D.R.
      Aging promotes neutrophil-induced mortality by augmenting IL-17 production during viral infection Heather Stout–Delgado,1.
      The same effect is noted in patients with asthma,
      • Camargo L.D.N.
      • Righetti R.F.
      • Aristóteles L.R.C.R.B.
      • et al.
      Effects of anti-IL-17 on inflammation, remodeling, and oxidative stress in an experimental model of asthma exacerbated by LPS.
      among smokers,
      • Montalbano A.M.
      • Riccobono L.
      • Siena L.
      • et al.
      Cigarette smoke affects IL-17A, IL-17F, and IL-17 receptor expression in the lung tissue: ex vivo and in vitro studies.
      diabetics,
      • Abdel-Moneim A.
      • Bakery H.H.
      • Allam G.
      The potential pathogenic role of IL-17/Th17 cells in both type 1 and type 2 diabetes mellitus.
      patients with heart conditions,
      • Du S.
      • Li Z.
      • Xie X.
      • et al.
      IL-17 stimulates the expression of CCL2 in cardiac myocytes via Act1/TRAF6/p38MAPK dependent AP-1 activation.
      ,
      • Mora-Ruíz M.D.
      • Blanco-Favela F.
      • Chávez Rueda A.K.
      • Legorreta-Haquet M.V.
      • Chávez-Sánchez L.
      Role of interleukin-17 in acute myocardial infarction.
      and men.
      • Legato M.
      Principes of Gender-Specifric Medicine Book.

      Specific IL-17 and SARS–CoV-2 Evidence

      There is emerging evidence supporting the role of IL-17 in SARS–CoV-2 pathogenesis, including a report on the first anatomopathologic lung analysis (with a high number of T helper-17 lymphocytes in the alveolar space)
      • Xu Z.
      • Shi L.
      • Wang Y.
      • et al.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      and two recent publications,

      Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: an emerging target of JAK2 inhibitor fedratinib [e-pub ahead of print]. J Microbiol Immunol Infect. https://doi.org/10.1016/j.jmii.2020.03.005, accessed May 7, 2020.

      ,

      Schett G, Sticherling M, Neurath MF. COVID-19: risk for cytokine targeting in chronic inflammatory diseases? Nat Rev Immunol. https://doi.org/10.1038/s41577-020-0312-7, accessed May 7, 2020.

      which reviewed the immune response in a patient with SARS–CoV-2 infection.

      Protumor Effect of IL-17 in Lung Cancer

      The role of IL-17 in lung cancer is well-recognized
      • Fabre J.
      • Giustiniani J.
      • Garbar C.
      • et al.
      Targeting the tumor microenvironment: the protumor effect of IL-17 related to cancer type.
      and it has been known to induce VEGF secretion in cancer cell lines.
      • Pan B.
      • Che D.
      • Cao J.
      • et al.
      Interleukin-17 levels correlate with poor prognosis and vascular endothelial growth factor concentration in the serum of patients with non-small cell lung cancer.
      This effect was dependent on the STAT3-GIV–associated protein pathway, which was abolished when the cells were exposed to a small interfering RNA.
      • Pan B.
      • Shen J.
      • Cao J.
      • et al.
      Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer.
      It was observed that those patients who had increased levels of serum IL-17 had poorer survival and enhanced angiogenesis compared with healthy controls.
      • Li C.
      • Yang P.
      • Sun Y.
      • et al.
      IL-17 response mediates acute lung induced by the 2009 pandemic influenza A (H1N1) virus.
      Furthermore, exposure of three different NSCLC cell lines to IL-17 has also been reported to increase neoangiogenesis and promote in vivo tumor growth in severe combined immunodeficient mice through a CXCR-2-dependent mechanism. IL-17 up-regulated several proangiogenic CXC chemokines, including CXCL1, CXCL5, CXCL6, and CXCL8. Inhibition of IL-17 with monoclonal antibodies abolished this up-regulation and could be potentially useful in patients with COVID-19 when other systemic therapies have been excluded.

      Potential Role of IL-17 Antibody in the Treatment of Patients With Lung Cancer and COVID-19

      The use of IL-17 antibody is well-recognized; it is currently approved in the treatment of psoriatic arthritis. Moreover, the therapeutic role of IL-17 antibodies has already been established not only in different cancer types
      • Fabre J.
      • Giustiniani J.
      • Garbar C.
      • et al.
      Targeting the tumor microenvironment: the protumor effect of IL-17 related to cancer type.
      but also in the treatment of lung infection with H1N1 virus,
      • Li C.
      • Yang P.
      • Sun Y.
      • et al.
      IL-17 response mediates acute lung induced by the 2009 pandemic influenza A (H1N1) virus.
      in acute respiratory distress syndrome,
      • Li J.T.
      • Melton A.C.
      • Su G.
      • et al.
      Unexpected role for adaptive αβTh17 cells in acute respiratory distress syndrome.
      ,
      • Righetti R.F.
      • Dos Santos T.M.
      • Camargo L.D.N.
      • et al.
      Protective effects of anti-IL17 on acute lung injury induced by LPS in mice.
      and pulmonary fibrosis.
      • Mi S.
      • Li Z.
      • Yang H.Z.
      • et al.
      Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-beta1-dependent and -independent mechanisms.
      From this analysis, and in the context of the global pandemic, there seem to be some theoretical elements to testing the potential utility of IL-17 antibodies in patients with lung cancer and COVID-19 in a clinical trial setting, with its potentially high social impact and given the lack of specific validated treatments.

      Potential Future Applications

      If a clinical trial is performed and it is found that the IL-17 target therapy can determine both the control of the tumor and resolution of SARS–CoV-2 infection, it can also be applied to other tumors in which IL-17 plays a role.

      Schett G, Sticherling M, Neurath MF. COVID-19: risk for cytokine targeting in chronic inflammatory diseases? Nat Rev Immunol. https://doi.org/10.1038/s41577-020-0312-7, accessed May 7, 2020.

      A clinical trial in patients without cancer could also provide opportune data specific to COVID-19 treatment.

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