Cancer and COVID-19: unravelling the immunological interplay with a review of promising therapies against severe SARS-CoV-2 for cancer patients

Abstract

Cancer patients, due to their immunocompromised status, are at an increased risk for severe SARS-CoV-2 infection. Since severe SARS-CoV-2 infection causes multiple organ damage through IL-6-mediated inflammation while stimulating hypoxia, and malignancy promotes hypoxia-induced cellular metabolic alterations leading to cell death, we propose a mechanistic interplay between both conditions that results in an upregulation of IL-6 secretion resulting in enhanced cytokine production and systemic injury. Hypoxia mediated by both conditions results in cell necrosis, dysregulation of oxidative phosphorylation, and mitochondrial dysfunction. This produces free radicals and cytokines that result in systemic inflammatory injury. Hypoxia also catalyzes the breakdown of COX-1 and 2 resulting in bronchoconstriction and pulmonary edema, which further exacerbates tissue hypoxia. Given this disease model, therapeutic options are currently being studied against severe SARS-COV-2. In this study, we review several promising therapies against severe disease supported by clinical trial evidence-including Allocetra, monoclonal antibodies (Tixagevimab-Cilgavimab), peginterferon lambda, Baricitinib, Remdesivir, Sarilumab, Tocilizumab, Anakinra, Bevacizumab, exosomes, and mesenchymal stem cells. Due to the virus's rapid adaptive evolution and diverse symptomatic manifestation, the use of combination therapies offers a promising approach to decrease systemic injury. By investing in such targeted interventions, cases of severe SARS-CoV-2 should decrease along with its associated long-term sequelae and thereby allow cancer patients to resume their treatments.

Keywords: COVID-19; Cancer; Hypoxia; IL-6; SARS-CoV-2; Therapeutics.

Fig. 1

COVID-19 Cancer Model. SARS-CoV-2 acts via both a direct and indirect pathway to induce systemic injury. The virus enters the body via ACE2 receptors on the cell surface of most of the organs resulting in invasion, replication, and damage. It causes a hypercoagulable state within the blood vessels and dyspnea within the lungs, which also secrete IL-6 that goes into the indirect pathway. In the indirect pathway, SARS-CoV-2 acts via PAMPs and DAMPs to activate antigen presenting cells (APCs) to secrete IL-6. Additionally, the virus activates pulmonary macrophages which secrete IL-6 directly and/or via IL-1. Malignancy and severe SARS-CoV-2 induce hypoxia, which is a trigger for IL-6 secretion. IL-6 activates downstream pathways to promote a pro-inflammatory state. Ultimately, this leads to increased cytokine release resulting in systemic inflammatory damage. The image of SARS-CoV-2 was derived from the Centers for Disease Control and Prevention (CDC) website: https://phil.cdc.gov/Details.aspx?pid=23312

Fig. 2

SARS-CoV-2 & Cancer-induced Hypoxia. SARS-CoV-2 and cancer induce hypoxia resulting in cellular necrosis and upregulation of the TLR4 pathway and HIF-1α. This results in increased secretion of IL-1β that stimulates NF-κB to cause mitochondrial dysfunction, secretion of reactive oxygen species and subsequent inflammation. IL-1β stimulates IL-1RI to cause alveolar macrophages pyroptosis to cause inflammatory damage. Hypoxia, IL-1β, and HIF-1α stimulate cyclooxygenase-2 (COX-2) which catalyzes the breakdown of arachidic acid into prostaglandin H₂ (PGH₂)_. Further breakdown with COX-1 and 2 results in the production of prostacyclin, prostaglandin, and thromboxane. Hypoxic metabolic derangements result in the accumulation of misfolded proteins within the lumen of the endoplasmic reticulum (ER) resulting in activation of the unfolded protein response (UPR). This activates inositol-requiring enzyme 1 (IRE-1), which catalyzes the transcription of X-box binding protein 1 (XBP-1) and results in secretion of IL-1β and IL-6, which turn on downstream pro-inflammatory pathways. Additionally, hypoxia activates protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK kinase) within the ER that stimulates activating transcription factor 4 (ATF4)-dependent transcriptional activation that results in secretion of IL-6 to promote inflammation. Additionally, HIF-1α, ATF4, and XBP-1 stimulate the release of vascular endothelial growth factor (VEGF). VEGF contributes to pulmonary inflammation and promotes vascular permeability resulting in pulmonary edema, which further exacerbates tissue hypoxia. The image of SARS-CoV-2 was derived from the Centers for Disease Control and Prevention (CDC) website: https://phil.cdc.gov/Details.aspx?pid=23312

Fig. 3

Hypercoagulability in Cancer & SARS-CoV-2. SARS-CoV-2 and cancer stimulate IL-6 secretion which causes endothelial cell dysfunction. This results in increased vascular permeability, complement activation, and inflammatory damage due to secretion of Acute Phase Reactants. Both SARS-CoV-2 and cancer contribute to Virchow’s Triad that, in addition to endothelial cell dysfunction, also includes blood stasis due to prolonged hospitalizations and hypercoagulability due to release of pro-coagulable factors. Ultimately, this results in a hypercoagulable state increasing the risk for DVTs and PEs. The image of SARS-CoV-2 was derived from the Centers for Disease Control and Prevention (CDC) website: https://phil.cdc.gov/Details.aspx?pid=23312

Fig. 4

Promising therapies against severe SARS-CoV-2. Known clinical pharmacological agents are currently being tested to assess their efficacy to combat severe SARS-CoV-2. Within the context of our proposed COVID-19 Cancer Model, their mechanism of action is being highlighted. The image of SARS-CoV-2 was derived from the Centers for Disease Control and Prevention (CDC) website: https://phil.cdc.gov/Details.aspx?pid=23312