key: cord-1003589-5qechg52 authors: Mohanty, Abhishek; Agnihotri, Shalini; Mehta, Anurag; Rawal, Sudhir title: COVID-19 and Cancer: Sailing Through The Tides date: 2021-03-26 journal: Pathol Res Pract DOI: 10.1016/j.prp.2021.153417 sha: 36c1b152952cb64bc92b3d81938c125220cd0be3 doc_id: 1003589 cord_uid: 5qechg52 The COVID-19 (coronavirus disease) pandemic caused by SARS-CoV-2 with its rapid expansion has led to extraordinary implications in our understanding of viral infections and their management globally. In this current scenario of unusual circumstances and public health emergency, the cancer care per se is facing unprecedented challenges. The peculiarity of the SARS-CoV-2 infections is still being uncovered as the pandemic spreads across the populations than showing signs of its curtailment. The review highlights the significance of idiosyncrasy of the SARS-Cov-2 infection especially putting forth the importance of immunosenescence, both in the COVID-19 specific immune response in the infected lungs of the elderly and in the cancer patients infected with SARS-CoV-2.The focus of the article is directed towards demystifying the unparalleled essence of a proprotein convertase, Furin in the biology of the SARS-Cov-2 infection and its role in facilitating viral transmission through expedited cellular entry into alveolar epithelial cells in COVID-19 infected cancer patients. The risk stratification of the cancer treatment and guidelines shaped up by national and international oncology societies in providing uncompromised patient care during the COVID-19 crisis have also been addressed. The global efforts towards vaccination in developing SARS CoV-2 immunity are also discussed in this article. with a history of cancer, particularly lung cancer (8) . The poorer cancer treatment outcomes in in this study exposed the increased risk of cancer patients towards COVID-19 related serious events, as evidenced with a ~3.5-fold increase in the risk of such COVID-19 positive cancer patients needing mechanical ventilation or ICU admission or dying compared with patients without cancer (OR 5.4, 95% CI 1. 8-16.2) . Therefore, with such drastic outcomes from COVID-19 infection liked to cancer, suggesting potentially that recent antineoplastic therapy may impair immunity, more intensive attention and surveillance or treatment should be paid to COVID-19 positive cancer patients, older patients or those with other comorbidities displaying rapid clinical deterioration. However, clinical data from China report that about 15-20% of patients have severe diseases with interstitial pneumonia, progressing to acute respiratory distress syndrome (ARDS) (9, 10) . Pneumonia includes decreased oxygen saturation, with severe bilateral ground glass abnormalities, patchy consolidation, and alveolar exudates (9, 10) .In such patients with ARDS, a spike in the levels of pro-inflammatory cytokines mediated characterizes the virus induced aberrant host immune response, which resembles the clinical and serological features of cytokine release syndrome (CRS). Cytokine Release Syndrome (CRS), a pathogen responsive innate immune activity, leading to an unrestrained release of cytokines like IL-6, IFN-γ or cytokine storm, was first documented in the year 1989, during the usage of anti-T cell antibody muromonab-CD3 in the treatment of solid organ transplantation (11) . CRS can influence fatal consequences leading to detrimental effects such as leakage from capillaries, tissue toxicity and edema, multiple organ failure and shock. The consequence of CRS include epithelial and endothelial cell apoptosis and vascular leakage, suboptimal T cell response (impaired virus clearance), accumulation of alternatively activated macrophages and altered tissue homeostasis, acute lung injury, and acute respiratory distress syndrome (ARDS) (12) . Usually, CRS is initiated by macrophages, dendritic cell, NK cell, and T cell, in response to pathogenassociated molecular patterns. CRS has been also observed in settings of T cell-engaging immunotherapy like CAR-T cell therapy (13) or anti-PD-1 therapy. Moreover, as compared to healthy controls, COVID-19 patients exhibit significantly higher levels of the exhausted marker J o u r n a l P r e -p r o o f PD-1 in their T cells (14) . Recent study also highlighted a significant decrease in T cells (especially CD8+ T cells) and increase in IL-6, IL-10, IL-2, and IFN-γ levels in the peripheral blood of severe COVID-19 cases compared to mild cases. Furthermore, the neutrophil-to-CD8+ T cell ratio were identified as the most powerful prognostic factor for severe COVID-19 (13, 15) . IFNγ may initiate cytokine storm in SARS patients (16) , while several cytokines including IL-6 may trigger CRS in COVID-19. Additionally, lympho-cytopenia may serve as the risk factor related to cytokine storm and disease severity (15) . It is not likely that cancer patients are still receiving immune-checkpoint inhibitors during this phase of the viral illness such as CRS. Over all, these recent results point out a major role of the host immune response, particularly of CRS, as a determining co-factor in the severe life-threaten form of COVID-19. Thus, treatment of CRS involves the use of both antiviral to control the underlying infection and immunosuppressive agents to dampen the aberrant pro-inflammatory response of the host. Unfortunately, there are currently no treatments directed at halting the cytokine storm remaining anti-IL-6 antibody, tocilizumab (under investigation) (17) and acute lung injury to stop the progression from manageable hypoxia to frank respiratory failure and ARDS in patients with COVID-19 infection (18) . Preventing progression from early acute hypoxia and cytokine release syndrome to frank hypoxic respiratory failure and ARDS could have a huge impact on the foreseeable overflow of the ICU units. To exacerbate further, the SARS-CoV-2 infections have also put forth an unusual clinical representation encompassing hypoxia development superfluous to patient's symptoms called silent hypoxia (19) . Silent hypoxia, the state of clinical deception by SARS-CoV-2 in symptomatically not connecting with the alarmingly low oxygen levels such as shortness of breath or signs of hypoxic unconsciousness in the COVID-19 patients has baffled the treating physicians all over the world (20, 21) . Happy or Silent hypoxia, a misnomer, is described as a scenario where patients who normally become breathless with oxygen saturation levels (SpO2) falling below 90 are happy and not in a state of breathlessness even with oxygen levels dipping 90 up to 70% as observed in COVID-19 patients with lung involvement. Nicholas D Caputo.et al also reiterates that prolonged and unaddressed hypoxia can lead to poor patient outcomes (22) . Astonishingly, these patients will still persist with functionally active lungs even with the high SARS-CoV-2 viral load affecting the lungs with no J o u r n a l P r e -p r o o f clues as to how the lungs move that they are able to blow off the carbon dioxide well so that they don't develop the shortness of breath. The patients with silent hypoxia generally seek medical care post 5-7 days of COVID-19 infection with the worst time of hypoxia, whether silent of not occurring at day 10 of infection. This "silent hypoxia" may be a clinical sign that providers can look for to determine if patients are at increased risk of sudden decompensation. Till date, there are no specific criteria to determine or outline the risk factors silent or happy hypoxia leaving some inconclusive correlations with severities of COVID-19 such as ARDS, with patients ending up on ventilators. In such situations, the lungs are very stiff, requiring higher pressures and higher oxygen levels to improve the hypoxemia while the mechanisms behind onset of hypoxemia in these individuals remains far from being lucid. The idiosyncrasies' of the COVID-19 specific Lung Immunity and Cancer: Biological The The incidence of severity of COVID-19 associated symptoms has been reported to have more extreme consequences in the elderly than the young. This vulnerability of the aging population J o u r n a l P r e -p r o o f towards COVID-19 infection could be attributed to the reduced ability of the immune system to generate antigen specific responses to pathogens and vaccination cumulatively amounting to the higher incidences of infection. One of the most profound and well acknowledged changes displayed by the aging immune system is termed immunosenescence, influencing both innate and adaptive immunity (23) (24) (25) . Age-associated regression or involution of thymus involving a decrease in tissue mass and cellularity resulting in loss of tissue organization leading to a net reduction in naive T cell output is believed to contribute radically toward immunosenescence (26) (27) (28) . This decline in naive T cell output due to age-dependent altered thymic activity is assumed to impact the properties on the peripheral T cell pool such alterations in phenotype and function, loss of diversity, and replicative senescence (29) (30) (31) (32) (33) . extremities is seen in elderly and the age predominance of the COVID-19 infection can be endorsed to the immune defense less state of the infected lungs deprived of naive T cells ( Figure 1a) . Hence, the decrease in the naïve T cells with age as shown by red circles in Figure 1a does not lead to total increase or visible presence of SARS CoV-2 specific effector T cells as represented by yellow circles (Figure 1a) . However, resident memory cells not specific to SARS CoV-2shown in blue circles in Figure 1a remain in increased numbers. In addition to the compromised SARS CoV-2 specific adaptive immune response, the SARS-CoV-2 results in a delayed dysregulated innate immune response owing to an inadequate production of Type 1 IFN which marks the hallmark of a cytokine mediated effective innate response mandatory for microbial killing against any pathogenic invasion. Put together, such an immune compromise state of the lungs predisposes it as primary site of COVID-19 infection. The earlier precedence in literature has strongly advocated the increased susceptibility of cancer patients to COVID-19 infection than those without cancer due to their immunosuppressive state ensued by malignancy and anti-cancer therapies like chemotherapy and surgery (35) .The immune evasive mechanisms adopted by tumor cells engages strategies to target the immune system especially the effector T cells (Teff) which are tuned by naive T cells to secrete cytokines, chemokines and to gain anti-tumor cytoxicity (36) . The anti-effector T cell mechanisms adopted by the tumor cells (36) ultimately result in the apoptosis of the effector T cells (Teff) leading to an immune disbalance or aberrant immune homeostasis , a state of compromised adaptive immune system contributed also by the immunosuppressive strategies adopted to combat cancer (Figure 1b) . As a consequence, the effector T cells represented by yellow circles (Figure 1 b) show diminishing levels ending up in immunosuppressive state. For instance , to make things worse, cancer treatment outcomes such as lymphopenia is commonly seen in cancer patients is by itself an independent poor prognosis indicator in COVID-19 The SARS-CoV-2 or 'the spiky invader' as it is named due to the involvement of surface glycoprotein, spike "S" protein in human infections, has acquired certain dissimilar but unique characteristic deviations from other Coronaviruses (CoVs) such as SARS-CoV and MERS-CoV. Structural studies of this heavily glycosylated, cell-surface spike (S) protein have exposed the presence of two functional domains, indispensable for host cellular entry, termed as S1 and S (37) . Furthermore, the recent literature also highlights the role of the receptor binding domain (RBD) on the S1 subunit of spike protein and its interaction and binding with host cellular receptor, ACE2, found on the lungs, arteries, heart, kidney, and intestines as principal mechanism responsible for entry of SARS-CoV-2 into lung alveolar epithelial cells (38) (39) (40) (41) . Another prerequisite of the viral entry as revealed is the activation or cleavage of the 'S' protein by the host proteases before the binding of the RBD to the host receptor (37) . In this regard, one of the most pivotal observations came from work by Hoffmann and colleagues in March 2020, showing that the pandemic SARS-CoV-2 harbors a functional polybasic cleavage site (RRAR) at the junction of S1 and S2 subunits or the S1/S2 cleavage site which is not found in closely related coronaviruses (4, 42) . The cleavage of S1/S2 site consequently permitting the Multiple studies indicate the that the over expression of host furin in many cancer cells, is a gain of function in tumor cells in attaching many viral particles due to more activation by furin and increased exposed RBD sites available for ACE2 interaction leading to heightened entrapment of SARS-CoV-2 in tumor cells (Figure 3b ) as compared to normal or healthy cells with ubiquitous expression of furin (Figure 3a,) . For instance, the literature documentations have raised concern for the increased susceptibility of the oral cancer patients On the contrary, treatment hindrance is not recommended in patients who are at high risk of disease progression with treatment delay including patients with rapidly progressive tumors with increase mortality risk, brain, leukemia, lymphoma, colon cancer, ovarian malignancy, and small cell lung cancer (Figure 4) . The need of the hour in the current stage of this unstoppable contagion is to focus on how the healthcare professionals can ensure a balance of uncompromised cancer care long with reduction of their patients' exposure to health-care facilities. The COVID-19 crisis has brought unprecedented challenges in the management of those who are afflicted, by overwhelming healthcare systems and causing great stress to the healthcare workforce providing care to immune-compromised cancer patients, amidst this pandemic, has been extremely challenging. As the pandemic accelerates, health care providers and their safety has become the prime area of concern. According to Remuzzi et al 20% of health-care workers were infected, and some have died (55) . In this global response, the safety of health-care workers must be ensured, thus strict measures (minimize chance for exposures, adhere to standard and transmission-based precautions, precautions while performing aerosol-generating procedures, implement engineering controls, train and educate health care personnel, implement environmental infection control etc ) and an adequate supply of leaky proof quality approved PPE is obligate to their preparedness to face the war against the COVID-19 positive patients (53) . The current situation investigates two fundamental prospects regarding welfare of patients. A novel coronavirus outbreak of global health concern Cultivation of viruses from a high proportion of patients with colds The COVID-19 epidemic The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Clinical features of patients infected with 2019 novel coronavirus in Wuhan Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China Review of the Clinical Characteristics of Coronavirus Disease 2019 (COVID-19) Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study Systemic reaction to the anti-T-cell monoclonal antibody OKT3 in relation to serum levels of tumor necrosis factor and interferon-gamma Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology Toxicities of chimeric antigen receptor T cells: recognition and management Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19) Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients An interferon-gamma-related cytokine storm in SARS patients Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study Respiratory Pathophysiology of Mechanically Ventilated Patients with COVID-19: A Cohort Study COVID-19 with silent hypoxemia COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome COVID-19 patients with respiratory failure: what can we learn from aviation medicine? Early Self-Proning in Awake, Non-intubated Patients in the Emergency Department: A Single ED's Experience During the COVID-19 Pandemic Immunosenescence: emerging challenges for an ageing population The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines Aging of the innate immune system Thymic involution with ageing: obsolescence or good housekeeping? Immunol Today Thymic involution and immune reconstitution Insights into thymic aging and regeneration Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? The origin and implication of thymic involution Understanding immunosenescence to improve responses to vaccines Why aging T cells fail: implications for vaccination Telomere dysfunction, autoimmunity and aging Human memory T cells: generation, compartmentalization and homeostasis Nosocomial infections in patients with cancer T-cell death and cancer immune tolerance Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Expression of angiotensin-converting enzyme 2 and proteases in COVID-19 patients: A potential role of cellular FURIN in the pathogenesis of SARS-CoV-2. Medical hypotheses Usul Afsar C. 2019-nCoV-SARS-CoV-2 (COVID-19) infection: Cruciality of Furin and relevance with cancer The proprotein convertase furin in tumour progression SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells The proprotein convertase furin is a pro-oncogenic driver in KRAS and BRAF driven colorectal cancer Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis Hypoxia enhances cancer cell invasion through relocalization of the proprotein convertase furin from the trans-Golgi network to the cell surface Radiotherapy-associated Furin Expression and Tumor Invasiveness in Recurrent Laryngeal Cancer Oral cancer and periodontal disease increase the risk of COVID 19? A mechanism mediated through furin and cathepsin overexpression A War on Two Fronts: Cancer Care in the Time of COVID-19 COVID-19 and Italy: what next? Radiation treatment in older patients: a framework for clinical decision making