The Society for Immunotherapy of Cancer perspective on regulation of interleukin-6 signaling in COVID-19-related systemic inflammatory response

Abstract

The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as 'cytokine storm'. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with COVID-19 with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. An immunology-informed approach may help identify alternative agents to modulate the pathological inflammation seen in patients with COVID-19. Drawing on extensive experience administering these and other immune-modulating therapies, the Society for Immunotherapy of Cancer offers this perspective on potential alternatives to anti-IL-6 that may also warrant consideration for management of the systemic inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19.

Keywords: immunomodulation; inflammation mediators.

Figure 1

Interleukin 6 (IL-6) signaling cascade. Antibodies such as tocilizumab, sarilumab and siltuximab inhibit IL-6 signaling by antagonizing ligand-receptor engagement, whereas Jakinibs prevent the downstream signaling cascade. The intracellular domain of gp130 is constitutively associated with the Janus family tyrosine kinases JAK1 and JAK2. On homodimerization, JAKs autophosphorylate and JAK1 phosphorylates 5 tyrosine residues in the cytoplasmic tail of gp130, leading to the activation of multiple intracellular signaling cascades. Recruitment and phosphorylation of STAT3 initiates its homodimerization and nuclear trafficking, initiating a transcriptional program associated with proliferation, differentiation, recruitment, survival and transformation in T and B cells and myeloid cells. A negative feedback loop modulates activation of the IL-6-JAK/STAT cascade, as STAT3 upregulates SOCS1 and SOCS3, which directly inhibits the catalytic activity of JAK by binding to phosphorylated gp130 at tyrosine 759, and stops JAK activation through direct binding. Phosphorylated gp130 is also a binding site for SH2 domain tyrosine phosphatase 2 (SHP2), activating a cascade involving RAS, RAF and mitogen-activated protein kinases (MAPK), which culminates in the activation of various transcription factors involved in increasing cell growth, antibody synthesis and acute phase protein generation. JAK also phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2), which is then phosphorylated by phosphoinositide 3-kinase (PI3K) to become phosphatidylinositol-3,4,5-trisphosphate (PIP3), which then phosphorylates PkB/Akt serine/threonine kinase to modulate expression of several genes involved in cellular survival.