**6. The biology of interconnection between COVID-19 and cancer**

The biological connection between COVID-19 and cancer remains an understudied area. However, age, ACE2, cytokine storm, and coagulopathy are few strong connecters that link COVID-19 with cancer. A better understanding of these linkers may help us find novel therapy options for the comorbidities.

#### **6.1 Age**

Our risk of getting cancer increases with age mostly due to accumulation of mutations with our prolonged exposure to mutagens. In addition, as we grow older, our body's immune system and DNA damage repair system get weaker [12]. In a similar fashion, age has turned out to be a poor prognostic factor for COVID-19 patients. This suggests that age plays a similar role in the progression and pathogenesis of cancer and COVID-19. Further studies should be conducted to identify the molecular interconnection between age, cancer and COVID-19.

#### **6.2 Angiotensin converting enzyme 2 (ACE2)**

ACE2 is a carboxypeptidase enzyme that converts angiotensin I to angiotensin 1–9 and angiotensin II to angiotensin 1–7. It is involved in the regulation of heart function and in the protection during acute lung injury [13–15]. SARS-CoV-2 enters human cells through angiotensin 1 converting enzyme 2 (ACE2) [16, 17]. The virus enters via this spike protein, binds to ACE2, and together with ACE2 enters the cell, fuses to the membrane, the virus exists the endosome, and replicates [18]. ACE2 is expressed in multiple organs, including cardiovascular, respiratory, urinary and digestive systems in healthy individuals. The expression levels of ACE2 in cellular subtypes is shown to be viral infection- and interferon-driven [19–21]. Notably, the expression levels of ACE2 are different in cancer cells. According to a recent clinical study, the expression levels of ACE2 gradually increase from healthy control, adenoma, to colorectal cancer patients. This indicates that cancer patients are more likely to be infected with SARS-CoV2. Patients with tumors, expressing higher levels of ACE2, are more susceptible to SARS-CoV2 infection and have poor prognosis [19, 22, 23]. Renal tissue shows higher expression levels of ACE2, and this might explain why most COVID-19 patients have renal dysfunction [18, 24]. Decreased levels of ACE2 were reported in non-small cell lung cancer (NSCLC), and its overexpression had a protective effect in NSCLC and breast cancer via inhibiting cell growth and angiogenesis [25–27]. Due to limited research done in this area, it would be worthwhile to test whether levels of ACE2 increases or decreases in various tissues of cancer patients and COVID-19 patients and how this impacts COVID-19 infection in these patients.

#### **6.3 Cytokine release syndrome**

Cytokine release syndrome (CRS) or cytokine storm is a systemic inflammatory response. Cytokine storm can be triggered by pathogenic infections, certain drugs, antibody treatments and, chimeric antigen receptor (CAR)-T cell therapy [28, 29]. Cytokine storm induction is the main cause of inflammation in SARS-CoV-2 infection. Upregulation of cytokines for example, interleukin-6 (IL-6), interleukin-1 beta (IL-1β) in serum, tumor necrosis factor-alpha (TNF-α) are found in COVID-19 patients. Elevated levels of lactate dehydrogenase, and increased levels of circulating monocytes are also common in COVID-19 patients [30, 31]. Such elevated levels of pro-inflammatory cytokines are also observed in cancer patients undergoing immunotherapy and CAR-T cell therapy [32]. The cytokine levels in cancer patients undergoing immunotherapy are higher than the cytokine levels in COVID-19 patients experiencing acute respiratory disease syndrome. The understanding of oncologists in regulating severe inflammatory reaction may prove highly beneficial in these settings. Therefore, anti-inflammatory therapies currently used for cancer patients may be repurposed for the treatment of COVID-19 patients.
