Cytokine Storms in Cancer and COVID-19

Abstract

During the COVID-19 pandemic, research on "cytokine storms" has been reinvigorated in the field of infectious disease, but it also has particular relevance to cancer research. Interleukin-6 (IL-6) has emerged as a key component of the immune response to SARS-CoV-2, such that the repurposing of anti-IL-6 therapeutics for COVID-19 is now a major line of investigation, with several ongoing clinical trials. We lay a framework for understanding the role of IL-6 in the context of cancer research and COVID-19 and suggest how lessons learned from cancer research may impact SARS-CoV-2 research and vice versa.

Figure 1

“Cytokine Storms” in Lung Cancer Tumorigenesis, CAR T Therapy, and SARS-CoV-2 Infection and Repurposed Anti-IL-6 Therapeutics for COVID-19 (A) IL-6 plays a key role in the detrimental systemic hyperactivated immune status characteristic of “cytokine storms.” IL-6 accumulates via other cytokines, including TNF-α. In lung cancer, it is produced by lung epithelial cells and exhausted tumor-associated CD8+ T lymphocytes. IL-6 acts on lung epithelial cells in inflammatory environments such as tobacco smoking. IL-6 is also a driver of CAR T-induced “cytokine storm” as a toxic therapy side effect and is associated with disease severity in COVID-19, where it is produced by monocyte-derived and recruited macrophages. In all of these settings, IL-6 is key to disease pathogenesis and a hallmark of poor prognosis. (B) BKT inhibition (Acalabrutinib) inhibits NF-κB signaling and results in decreased IL-6 production. Corticosteroids (Dexamethasone) inhibit TNF-α-mediated IL-6 mRNA expression and protein secretion by decreasing IL-6 mRNA stability. IL-6R monoclonal antibodies (Tocilizumab, Siltuximab) dampen both the classic and the trans-signaling IL-6 pathways to suppress IL-6-JAK-STAT signaling. All of these approaches are currently under investigation in clinical trials to treat COVID-19. Figures were created using biorender.com.