Cyclin‑dependent kinase 9 expression and its association with CD8+ T cell infiltration in microsatellite‑stable colorectal cancer

Abstract

Programmed death 1 (PD-1)-targeted therapy has benefited patients with microsatellite instability-high metastatic colorectal cancer (mCRC). However, the efficacy of PD-1-targeted therapy is poor in patients with microsatellite-stable (MSS) mCRC. Therefore, it is imperative to explore additional co-inhibitory molecular signalling pathways to improve the efficacy of immunotherapy in MSS mCRC treatment. In the present study, the association between cyclin-dependent kinase 9 (CDK9) expression and the survival of patients with CRC was analysed using RNA sequencing data from 605 patients, including 121 cases of mortality, from human cancer datasets. Furthermore, 35 clinical MSS stage III–IV CRC specimens were collected to assess CDK9 protein expression by immunohistochemistry, and the frequency of tumor-infiltrating CD8+ T cells was assessed by flow cytometry. The human cancer datasets demonstrated that upregulation CDK9 significantly shortened the survival of patients with stage II–IV colon cancer. Additionally, CDK9 mRNA expression was positively correlated with the expression levels of genes associated with immune evasion in the tumor. Notably, CDK9 was expression was upregulated in stage IV CRC compared with para-cancerous tissues and early-stage tumors. Interestingly, CDK9 expression was negatively associated with the infiltration of CD8+ T cells at the tumor site. In addition, the expression levels of T-cell immunoglobulin mucin family member 3 and CD39, proteins associated with exhaustion, on tumor-infiltrating CD8+ T cells were significantly elevated in patients with abnormal CDK9 expression levels. The present study demonstrated that CDK9 expression was negatively associated with CD8+ T cell infiltration and positively associated with CD8+ T cell exhaustion in MSS mCRC. In conclusion, CDK9 may be utilized to evaluate the prognosis and the immune-type of the tumor microenvironment in patients with MSS mCRC.

Cyclin-Dependent Kinase Inhibitors and Their Therapeutic Potential in Colorectal Cancer Treatment

“…Most important, CDK5 is directly involved in the degradation of the cell cycle inhibitor p21 and can enhance CDK2 activity, which might further promote tumor cell growth ( Huang et al, 2016 ). Decreased survival rates are also observed in CRC patients with high CDK9 and CDK13 levels ( Kim et al, 2012 ; Wang et al, 2019 ). Interestingly, high CDK9 expression in CRC tissue was negatively correlated with cytotoxic CD8 + T cell infiltration.…”

“…Interestingly, high CDK9 expression in CRC tissue was negatively correlated with cytotoxic CD8 + T cell infiltration. Furthermore, these infiltrated cells showed increased cell exhaustion in CDK9-high tumors, which might further affect patient outcome ( Wang et al, 2019 ). Last, CDK8 overexpression in CRC is also considered as a marker for poor patient prognosis, being directly linked to β-catenin activation amongst others and therefore promoting cancer growth ( Firestein et al, 2008 ; Firestein et al, 2010 ; Seo et al, 2010 ).…”

Long noncoding RNA LINC01578 drives colon cancer metastasis through a positive feedback loop with the NF‐κB/YY1 axis

“…Next, the livers were resected and liver metastases were detected by hematoxylin and eosin (H&E) staining. The liver metastatic lesions were further used to perform immunohistochemistry (IHC) staining as previously described [36] with primary antibodies against Ki67 (Cat. ab16667; Abcam), p50 (Cat.…”

Left-Sided Colorectal Cancer Distinct in Indigenous African Patients Compared to Other Ethnic Groups in South Africa.

“…It has been well established that the increased tumour-in ltrating CD4 + and CD8 + T cells in patients with MSI-H CRC (due to the increased mutator phenotype of the tumour stimulating the host immune response) signi cantly improved patient outcomes when treated with immunotherapy when compared to MSS CRC with decreased immune response. 59,60 The study by Carethers et al 2014 illustrate despite having the same disease subtype and stage, ethnicity can be a negative prognostic factor in CRC disease.…”