The high expression of key components of inflammasome and pyroptosis might lead to severe COVID-19 infection in cancer patients.

Dear editor,

Previous studies found that both the incidence of corona virus disease 2019 (COVID-19) infection and the severe rate were high in cancer patients. , Recent papers showed that the high expression level of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) host factors including the receptor and entry factors in cancer tissues could partially explain the COVID-19 susceptibility of cancer patients. , However, why patients with cancer infected by SARS-CoV-2 more likely develop severe symptoms is not clear.

In severe COVID-19 patients, SARS-CoV-2 infection activated the nucleotide oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome and leads to the excessive production of pro-inflammatory cytokines known as cytokine storm and activation of pyroptosis. In current study, we aim to investigate the gene expression level of the key components of inflammasome and pyroptosis pathways in normal and cancer tissues in the TCGA database from Gene Expression Profiling Interactive Analysis (GEPIA).

The centrosomal serine/threonine kinase NIMA-related kinase 7 (NEK7) plays a scaffolding function in NLRP3 activation. Expression of NEK7 was significantly up-regulated in cholangiocarcinoma (CHOL), esophageal carcinoma (ESCA), lower-grade glioma (LGG), pancreatic adenocarcinoma (PAAD), stomach adenocarcinoma (STAD), and thymoma (THYM), while NEK7 was down-regulated in adrenocortical carcinoma (ACC), uterine corpus endometrial carcinoma (UCEC) and uterine carcinosarcoma (UCS) (Fig. 1 A). For the intracellular inflammasome sensor NLRP3, the mRNA expression was increased in kidney renal clear cell carcinoma (KIRC), acute myeloid leukemia (LAML) and PAAD, while NLRP3 expression was down-regulated in diffuse large B-cell lymphoma (DLBC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) and THYM (Fig. 1B).

Fig. 1

The expression levels of key components of NLRP3-inflammasome and pyroptosis including NEK7 (A), NLRP3 (B), CASP1 (C), ASC (D) and GSDMD (E) in cancer patients. ns, no significance; ∗, P < 0.05.

Caspase-1 (CASP1) was activated by NLRP3 to catalyze proteolytic cleavage of pro-interleukin-1β (pro-IL-1β) and pro-IL-18. The expression levels of CASP1 in normal and cancer tissues were analyzed. In cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), glioblastoma multiforme (GBM), KIRC, kidney renal papillary cell carcinoma (KIRP), LAML, LGG, PAAD, STAD and testicular germ cell tumors (TGCT), the expression level of CASP1 was increased significantly, while CASP1 expression was decreased in kidney chromophobe (KICH), LUAD, prostate adenocarcinoma (PRAD), and THYM (Fig. 1C).

Adapter protein apoptosis-associated speck-like protein containing a CARD (ASC) was required during CASP1 activation. The expression of ASC in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), CESC, CHOL, colon adenocarcinoma (COAD), GBM, KIRC, KIRP, LAML, LGG, liver hepatocellular carcinoma (LIHC), PAAD and UCEC were significantly higher than that in normal tissues (Fig. 1D). Interestingly, no cancer tissue contains lower expression level of ASC compared with normal tissues within the scope of current study.

Cleaved gasdermin D (GSDMD) forms pores at the plasma membrane which allows for the release of IL-18, IL-1β and the influx of ions leading to pyroptosis. GSDMD was up-regulated in CHOL, DLBC, GBM, head and neck squamous cell carcinoma (HNSC), LAML, PAAD, skin cutaneous melanoma (SKCM) and THYM, while GSDMD was down-regulated in ACC, KICH, LUSC, ovarian serous cystadenocarcinoma (OV), pheochromocytoma and paraganglioma (PCPG) and PRAD (Fig. 1E).

The symptoms of COVID-19 infection could be asymptomatic, mild, or severe. Studies have shown that cytokine storm induced by NLRP3-inflammasome caused more severe disease in COVID-19 patients. We found that ASC was up-regulated in all cancer types in current study, which could partially explain the severe symptoms in cancer patients. Interestingly, all five key components of NLRP3-inflammasome and pyroptosis we examined in this study were up-regulated in LAML and PAAD (Fig. 2 A and 2B), indicating the high severe COVID-19 rate in those two types of cancer patients infected with SARS-CoV-2. Previous studies explained the high infection rate of cancer patients through SARS-CoV-2 host factors. Here, we linked the COVID-19 severe symptoms to the up-regulation of key components of NLRP3-inflammasome and pyroptosis. Our results advanced the understanding on the link between COVID-19 and cancer, which will further alert the public to pay more careful attention to the patients with COVID-19.

Fig. 2

All five key components of NLRP3-inflammasome and pyroptosis we examined were up-regulated in LAML (A) and PAAD (B) patients.

Declaration of Competing Interest

The authors declare that there are no conflicts of interest.