key: cord-0832301-68o7g6k7 authors: du Plessis, M; Fourie, C; Riedemann, J; de Villiers, WJS; Engelbrecht, AM title: Cancer and Covid-19: Collectively Catastrophic date: 2021-10-23 journal: Cytokine Growth Factor Rev DOI: 10.1016/j.cytogfr.2021.10.005 sha: 40f0ae4c071271bfab762d02dc744ccd49b77666 doc_id: 832301 cord_uid: 68o7g6k7 The Covid-19 pandemic has spread rapidly across the globe, resulting in more than 3 million deaths worldwide. The symptoms of Covid-19 are usually mild and non-specific, however in some cases patients may develop acute respiratory distress syndrome (ARDS) and systemic inflammation. Individuals with inflammatory or immunocompromising illnesses, such as cancer, are more susceptible to develop ARDS and have higher rates of mortality. This is mediated through an initial hyperstimulated immune response which results in elevated levels of pro-inflammatory cytokines and a subsequent cytokine storm. This potentiates positive feedback loops which are unable to be balanced by anti-inflammatory mediators. Therefore, elevated levels of IL-1β, as a result of NLRP3 inflammasome activation, as well as IL-6 and TNF-α amongst many others, contribute to the progression of various cancer types. Furthermore, Covid-19 progression is associated with the depletion of CD8(+) and CD4(+) T cells, B cell and natural killer cell numbers. Collectively, a Covid-19-dependent pro-inflammatory profile and immune suppression promotes the optimal microenvironment for tumourigenesis, initiation and immune evasion of malignant cells, tumour progression and metastasis as well as cancer recurrence. There are, however, therapeutic windows of opportunity that may combat both Covid-19 and cancer to improve patient outcomes. TNF-α is a pro-inflammatory cytokine which plays a major role during adaptive immunity. However, TNF-α is also one of the major dysregulated pro-inflammatory cytokines present in the TME (Ham et al., 2016) . The role of TNF-α in cancer is considered to be a double-edged sword. TNF-α can act as an effector molecule in cell-mediated killing of cancer cells or it can promote tumour survival through cancer-promoting inflammation (Balkwill, 2009 ). However, increasing evidence suggests that TNF-α is involved in all stages of tumourigenesis and elevated levels of TNF-α in the TME is an indicator of poor prognosis. TNF-α can activate two receptors, TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (Aggarwal, 2003 2020) . Furthermore, the cytokine storm promotes the release other pro-inflammatory cytokines, such as IL-2, IL-12 and MCP-1, which perpetuates a proinflammatory and pro-invasive positive feedback loop in the TME (Johnson & Laloraya, 2020) . Covid-19 infection may also induce inflammasome activation, which is a major contributor to the proinflammatory profile seen during disease progression. Taking these findings into consideration, it is plausible that IL-1β plays a major role in acute lung injury induced by respiratory viral infections, therefore pharmacologic targeting of this pathway may have beneficial effects. It has been observed that injury of type II alveolar epithelial cells that express ACE2 results in inflammasome activation . The acute immune response to SARS-CoV-2 infection is mainly driven by inflammatory alveolar and monocyte-derived macrophages, which is activated by PAMPs/DAMPs released by infected and apoptotic pneumocytes (Fung et al., 2020) . The SARS-CoV-2 pandemic is spreading in a world where cancer prevalence is also rapidly growing, which raises questions as to how they could potentially interact with one another. As mentioned previously, the main risk factors of severe Covid-19 in the general population are gender, advanced age, obesity and diseases such as coronary heart disease, diabetes, hypertension and cancer. Cancer Intracellular infection (Barber et al., 2006) . IL-6 inhibitors may benefit cancer and Covid-19 patients due to the dual role that IL-6 plays in these diseases. Tocilizumab and Siltuximab are monoclonal antibodies that target the IL-6 receptor (IL-R). Tocilizumab has been approved for the treatment of rheumatoid arthritis patients, with no off-target effects, and may dampen the cytokine storm (Biran et al., 2020) . Siltuximab has been used for the treatment of cancer patients and inhibits STAT3 and MAPKs, which resulted in significant antitumor effects. Furthermore, Siltuximab has been tested in Covid-19 patients, and successfully decreased levels of IL-6 and CRP in these patients while improving disease outcomes. The use of the corticosteroid, dexamethasone, in Covid-19 patients resulted in reduced mortality risk. Furthermore, corticosteroids have been reported to inhibit the production of IL-6 and TNF-α-mediated IL-6 production (Turnquist et al., 2020) . The effects of corticosteroids on cancer remains uncertain, however is has been shown that glucocorticoids inhibit the development of lymphoids and has antiinflammatory effects (Horby et al., 2020) . Napabucasin is a well-known inhibitor of cancer cell stemness and has been reported to inhibit STAT3 and ROS-mediated angiogenesis (Bharadwaj et al., Nagaraju et al., 2020) . Furthermore, the use of melatonin as an adjuvant treatment to cancer has been well established and it has recently been suggested as an adjuvant treatment for Covid-19 patients. Melatonin has indirect anti-viral effects by inhibiting the excessive production of pro-inflammatory cytokines, ROS production and the J o u r n a l P r e -p r o o f over activation of the immune system (Zhang et al., 2020) . Therefore, the anti-inflammatory, antioxidant and immunomodulatory effects may benefit patients with cancer and Covid-19. Excessive inflammation induced by the NLRP3 inflammasome in many diseases, including cancer, can be detrimental and the inhibition thereof is a promising approach for cancer prevention and treatment. Based on these above-mentioned studies, it could also alleviate the devastating effects of Covid-19 in these patients. By taking advantage of the complex signaling cascade of the NLRP3 inflammasome, a diverse range of targets can be used for its inhibition. This includes but is not limited to: inhibiting NLRP3 inflammasome activation, suppressing upstream signals, blocking inflammasome assembly, inhibiting caspase-1 activation and neutralizing inflammatory cytokines produced by the inflammasome, like IL-1β. Drugs already used in clinical applications include thalidomide, a drug that targets and inhibits the activation of caspase-1, which is mainly used as a sedative to treat anxiety, insomnia and gastritis (Miller, 1991) . For the treatment of multiple myeloma, thalidomide has been approved for first-line therapy in combination with other chemotherapeutic drugs, which exerts anti-tumour effects (Breitkreutz & Anderson, 2008) . It has been suggested that the mechanism of malignancy control with thalidomide is attributed to its anti-angiogenic activity, by reducing angiogenic factors like fibroblast growth factor (FGF) and vascular endothelial factor (VEGF) (Figg et al., 2002) . However, in a randomized, double-blinded, placebo-controlled trial, patients with advanced non-small lung cell cancer were treated with thalidomide in combination with gemcitabine and carboplatin. The study showed that the treatment regime did not improve the survival rate of these patients. However, it did increase the risk of thrombotic events (Lee et al., 2009 ). Anakinra is a recombinant form of interleukin-1 receptor antagonist (IL-1Ra), which is commonly utilized in the treatment of autoinflammatory diseases and rheumatoid arthritis (Dinarello, 2009 ). Previous studies with myeloma cells have shown that anakinra significantly reduces IL-6 levels but Canakinumab is a human monoclonal antibody that targets IL-1β but not IL-1α. The use of canakinumab has not been studied significantly in cancer, but during a randomized, double-blinded, placebo-controlled trial of patients with lung cancers and atherosclerosis, researchers found that canakinumab significantly decreased lung cancer mortality by targeting the IL-1β innate immunity pathway (Ridker et al., 2017) . The use of canakinumab as an anti-tumour drug has mainly focused on lung cancer and is being studied in phase III clinical trials in non-small lung cancer. The cytokine release inhibitory drug, CRID3, also known as MCC950, is a diarylsulfonylureacontaining compound that inhibits the activation of the NLRP3 inflammasome, in mice in vivo and in human cells in vitro (Coll et al., 2015) . In a spontaneous chronic colitis mouse model, MCC950 significantly suppressed IL-1β secretion and caspase-1 activation, which indicates its potential use as an anti-tumour therapeutic agent (Perera et al., 2018) . Covid-19 infection is a serious and often deadly condition and significantly more so for patients with underlying conditions such as cancer. The unique inflammatory cascades associated with Covid-19 including excessive inflammation, inflammasome activation, exhaustion of immune function and the aberrant activation of several signalling pathways creates an optimal environment for malignant transformation and progression. This could also be true for dormant cancer cells and pre-malignant cell transformation. These effects may also contribute to resistance of cancer cells to cancer therapies. We have discussed various treatments that may prove effective against the pro-inflammatory effects of Covid-19 as well as cancer. These treatments may contribute to the resolution of Covid-19 infection and may protect against the development, progression and recurrence of cancerous cells during and following Covid-19 infection. Not Applicable. All authors have approved the contents of this paper and have agreed to the submission policies. Not applicable. To the best of our knowledge, we have no conflicts of interest to disclose. All authors confirm that this work is original and has not been published elsewhere, nor is it currently under consideration for publication elsewhere. J o u r n a l P r e -p r o o f The financial assistance of the National Research Foundation (NRF) of South Africa (118566), SAMRC and CANSA towards this research is hereby acknowledged. Opinions expressed and conclusions arrived at, are those of the authors and are not necessarily to be attributed to the NRF, SAMRC or CANSA. Each author has substantially contributed to conducting the underlying research and drafting this manuscript. Not applicable. The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management Cancer and COVID-19: Unmasking their ties Targeting infl ammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe Signalling pathways of the TNF superfamily: a double-edged sword Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment The NF-kappa B and I kappa B proteins: new discoveries and insights Tumour necrosis factor and cancer Restoring function in exhausted CD8 T cells during chronic viral infection Targeting potential drivers of COVID-19: neutrophil extracellular traps Inflammasomes: current understanding and open questions Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression Toward understanding the 2019 Coronavirus and its impact on the heart The role of oxidative stress in rhinovirus induced elaboration of IL-8 by respiratory epithelial cells, Free Radic Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study Imbalanced host response to SARS-CoV-2 drives development of COVID-19 The clinical significance of serum and bronchoalveolar lavage inflammatory cytokines in patients at risk for acute respiratory distress syndrome Patterns of cell cycle checkpoint deregulation associated with intrinsic molecular subtypes of human breast cancer cells Activation of NF-κB by extracellular S100A4: analysis of signal transduction mechanisms and identification of target genes Thalidomide in multiple myeloma--clinical trials and aspects of drug metabolism and toxicity Stat3 as an oncogene Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases Inflammatory factor TNF-alpha promotes the growth of breast cancer via the positive feedback loop of TNFR1/NF-kappaB (and/or p38)/p-STAT3/HBXIP/TNFR1 Interferon-gamma at the crossroads of tumor immune surveillance or evasion Mitochondrial reactive oxygen species trigger hypoxia-induced transcription Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Cytokine responses in severe acute respiratory syndrome coronavirusinfected macrophages in vitro: possible relevance to pathogenesis Middle East respiratory syndrome coronavirus efficiently infects human primary T lymphocytes and activates the extrinsic and intrinsic apoptosis pathways A small molecule inhibitior of the NLRP3 inflammasome is a potential therapeutic for inflammatory diseases Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and 1016/j Breast cancer stem cells as drivers of tumor chemoresistance, dormancy and relapse: new challenges and therapeutic opportunities Inflammation triggers Zeb1-dependent escape from tumor latency Coronavirus virulence genes with main focus on SARS-CoV envelope gene Early use of steroids affects immune cells and impairs immunotherapy efficacy. ESMO open The immuno-oncological challenge of COVID-19 The role of intratumoral and systemic IL-6 in breast cancer Reduction and functional exhaustion of T cells in patients with Coronavirus Disease 2019 (COVID-19) Immunological and inflammatory functions of the interleukin-1 family Virus-induced double-membrane vesicles Inhibition of angiogenesis: treatment options for patients with metastatic prostate cancer Cytokine storm during chemotherapy: a new companion diagnostic emerges? Signal transduction by reactive oxygen species Immuno-onology: understanding the function and dysfunction of the immune system in cancer COVID-19: a potential driver of immunemediated breast cancer recurrence Inflammaging: An evolutionary perspective on immunosenescence Targeting the NLRP3 inflammasome in severe covid-19 Understanding SARS-CoV-2-mediated inflammatory responses: from mechanisms to potential therapeutic tools A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor Hyper-Activation of STAT3 Sustains Progression of Non-Papillary Basal-Type Bladder Cancer via FOSL1 Regulome NF-kappaB activation by reactive oxygen species: fifteen years later Inflammation and oncogenesis: a vicious connection Inflammatory cytokines in cancer: tumour necrosis factor and interleukin take the stage Intracellular signals and events activated by cytokines of the tumor necrosis factor superfamily: From simple paradigms to complex mechanisms Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis Targeting inflammasome/IL-1 pathways for cancer immunotherapy Transcription factor ATF2 regulation by the JNK signal transduction pathway Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis Regulation of NF-κB by TNF family cytokines Expression of elevated levels of proinflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor How COVID-19 induces cytokine storm with high mortality Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report Clinical features of patients infected with 2019 novel coronavirus in Wuhan Dysregulation of SOCS-mediated negative feedback of cytokine signaling in carcinogenesis and its significance in cancer treatment A cytokine super cyclone in COVID-19 patients with risk factors: the therapeutic potential of BCG immunization STAT3 signaling: anticancer strategies and challenges Role of STAT3 in Cancer Metastasis and Translational Advances Nuclear factor-kappaB in cancer development and progression The regulation of AP-1 activity by mitogen-activated protein kinases A panoramic review of IL-6: Structure, pathophysiological roles and inhibitors Circulating levels of infl ammatory cytokines and risk of colorectal adenomas The PAK1-Stat3 signaling pathway activates IL-6 gene transcription and human breast cancer stem cell formation Loss of STAT1 from mouse mammary epithelium results in an increased neu-induced tumor burden SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is further increased by a naturally occurring elongation variant Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists STAT3 mediates myeloid cell-dependent tumor angiogenesis in mice TGFbeta1-induced PAI-1 gene expression requires MEK activity and cell-to-substrate adhesion The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells Randomized doubleblind placebo-controlled trial of thalidomide in combination with gemcitabine and Carboplatin in advanced non-small-cell lung cancer Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19 PTEN mutation: many birds with one stone in tumorigenesis Family Cytokines in Hepatocellular Carcinoma SARS-CoV-2 is sensitive to type I interferon pretreatment Inflammation and ovarian cancer The role of interleukin-6 in the evolution of ovarian cancer: clinical and prognostic implications--a review COVID-19 and cytokine storm syndrome: can what we know about interleukin-6 in ovarian cancer be applied AKT/PKB signaling: navigating downstream Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus An abberant STAT pathway is central to COVID-19 AP-1 a target for cancer prevention CD8 T cell exhaustion during chronic viral infection and cancer COVID-19: consider cytokine storm syndromes and immunosuppression The good and the bad faces of STAT1 in solid tumours Thalidomide embryopathy: a model for the study of congenital incomitant horizontal strabismus p53 isoforms regulate aging-and tumor-associated replicative senescence in T lymphocytes Interleukin-1b maturation triggers its relocation to the plasma membrane for gasdermin-Ddependent and independent secretion Role of the NLRP3 inflammasome in cancer Invasive potential induced under long-term oxidative stress in mammary epithelial cells Antioxidants as well as oxidants activate c-fos via Ras-dependent activation of extracellular-signal-regulated kinase 2 and Elk-1 Napabucasin (BBI 608), a potent chemoradiosensitizer in rectal cancer The role of NFkB in drug addiction: beyond inflammation Endothelialmesenchymal transition in normal human esophageal endothelial cells cocultured with esophageal adenocarcinoma cells: role of IL-1beta and TGF-beta2 Lung histopathological findings in fatal pandemic influenza A (H1N1) A double edged sword of immune regulation and cancer progression Type I and type III interferons-induction, signaling, evasion, and application to combat COVID-19 MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice Evaluation of COVID-19 based on ACE2 expression in normal and cancer patients Oxidative stress, inflammation, and cancer: How are they linked? Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial inants of COVID-19 disease severity in patients with cancer Combination of CTLA-4 and PD-1 blockers for treatment of cancer TNF-alpha enhances estrogen-induced cell proliferation of estrogen dependent breast tumor cells through a complex containing nuclear factor-kappa B Principles and properties of ion flow in P2X receptors The emerging roles of macrophages in cancer metastasis and response to chemotherapy Anti-PD-1 and Anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma an NF-kappaB inhibitor, suppresses tumor growth and enhances response to chemotherapy in gastric cancer Suppression of lymphoma and epithelial malignancies effected by interferon gamma Immune surveillance of tumours The NLRP3 inflammasome: molecular activation and regulation to therapeutics Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection PTEN and p53: who will get the upperhand Fine-tuning of type I interferon response by STAT3 Cytokine storms in cancer and covid-19 The landscape of human cancer proteins targeted by SARS-CoV-2 Cytokines in colitis associated cancer: potential drug targets? Inflamm Allergy Drug Targets Structure, function, and antigenicity of the SARSCoV-2 spike glycoprotein STAT3 regulates the type I IFNmediated antiviral response by interfering with the nuclear entry of STAT1 Loss of tumour suppressor gene function in human cancer: an overview Silencing STAT3 may inhibit cell growth through regulating signalling pathway, telomerase, cellcycle, apoptosis and angiogenesis in hepatocellular carcinoma: potential uses for gene therapy STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor Clusterin confers resistance to TNF-alphainduced apoptosis in breast cancer cells through NF-kappaB activation and Bcl-2 overexpression Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain Components of the interleukin-6 transsignalling system are associated with the metabolic syndrome, endothelial dysfunction and arterial stiffness TOR signaling in growth and metabolism Attenuated interferon and proinflammatory response in SARSCoV-2-infected human dendritic cells is associated with viral antagonism of STAT1 phosphorylation COVID-19: immunopathogenesis and Immunotherapeutics. Signal transduction and targeted therapy Role of PI3K/Akt and MEK/ERK in mediating hypoxiainduced expression of HIF-1α and VEGF in laser-induced rat choroidal neovascularization Reactive oxygen species in the immune system SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists Low concentration of uncouplers of oxidative phosphorylation decreases the TNF-induced endothelial permeability and lethality in mice STAT3-decoyoligodeoxynucleotide inhibits the growth of human lung cancer via down-regulating its target genes NLRP3 inflammasome-a key player in antiviral responses Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients Plasminogen activator inhibitor 1 promotes immunosuppression in human non-small cell lung cancers by enhancing TGF-β1 expression in macrophage Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium