Abstract
Severe coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by pneumonia, lymphopenia, and cytokine storms. Patients with underlying conditions, and especially cancer patients with impaired immunity, are particularly vulnerable to SARS-CoV-2 infection and complications. Although angiotensin converting enzyme II (ACE2) has been identified as a cellular binding receptor for SARS-CoV-2, immunopathological changes in severe cancer patients support the investigation of additional potential receptors such as dipeptidyl peptidase 4 (DPP4), a key immunoregulator. However, a comprehensive profiling analysis of DPP4 in malignancies remains obscure. In this study, using different datasets, we demonstrated the expression of DPP4 in healthy tissues and pan-cancers, showing the risk of different cancer types towards SARS-CoV-2 infection according to DPP4 expression levels. DPP4 expression was positively correlated with infiltrating levels of various immune cells and showed strong correlations with diverse immune marker sets in pan-cancer patients analyzed by Tumor Immune Estimation Resource (TIMER). These findings suggest that increased DPP4 expression in specific cancer patients might account for the high susceptibility to SARS-CoV-2 infection and the induction of cytokine storms. Due to the critical role of DPP4 in immunometabolism, our results indicate that pharmacological inhibition of DPP4 might provide beneficial therapeutic effects for SARS-CoV-2 treatment together with other strategies in specific tumor patients.
Highlights
Coronavirus disease 2019 (COVID-19), a newly emerged respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic with 21,294,845 cases and 761,779 deaths as of August 16, 2020 [1]
It is intriguing that adipose tissue demonstrated abundant dipeptidyl peptidase 4 (DPP4) expression in the GTEx dataset, which is consistent with the current concept that obese patients are susceptible to SARSCoV-2 infection (Figure 1B)
DPP4 is a functional receptor of MERS-CoV; the receptorbinding S1 domain of the MERS-CoV spike protein was copurified with DPP4 from lysates of susceptible Huh-7 cells
Summary
Coronavirus disease 2019 (COVID-19), a newly emerged respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic with 21,294,845 cases and 761,779 deaths as of August 16, 2020 [1]. Cancer patients with defective immunity are especially susceptible to SARS-CoV-2 infection [4]. It has been shown that obese or specific cancer patients are more susceptible to SARS-CoV-2 infection, mainly due to the high expression of ACE2 [8, 9]. DPP4 was identified as a functional receptor of Middle East respiratory syndrome coronavirus (MERS-CoV) because the receptor-binding domain (RBD) of the MERS-CoV spike protein copurified with DPP4 from cell lysates. A docked model of SARSCoV-2 predicted that its spike protein S1 domain interacted with DPP4 residues in close proximity to the active region of the S1 domain in SARS-CoV-2. Additional DPP4 residues (Q286, I287, N338, V341, and R336) were predicted to interact with the S1 domain of the spike protein of SARS-CoV-2 [13]
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