CD8+ T cell-associated genes MS4A1 and TNFRSF17 are prognostic markers and inhibit the progression of colon cancer

Ye Song; Zhipeng Zhang; Bo Zhang; Weihui Zhang

doi:10.3389/fonc.2022.941208

CD8+ T cell-associated genes MS4A1 and TNFRSF17 are prognostic markers and inhibit the progression of colon cancer

Front Oncol. 2022 Sep 20:12:941208. doi: 10.3389/fonc.2022.941208. eCollection 2022.

Authors

Ye Song^{1

2}, Zhipeng Zhang^{1

2}, Bo Zhang^{1

2}, Weihui Zhang^{1

2}

Affiliations

¹ Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
² Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

Abstract

Background: Colon cancer (CC) is among the top three diseases with the highest morbidity and mortality rates worldwide. Its increasing incidence imposes a major global health burden. Immune checkpoint inhibitors, such as anti-PD-1 and anti-PD-L1, can be used for the treatment of CC; however, most patients with CC are resistant to immunotherapy. Therefore, identification of biomarkers that can predict immunotherapy sensitivity is necessary for selecting patients with CC who are eligible for immunotherapy.

Methods: Differentially expressed genes associated with the high infiltration of CD8+ T cells were identified in CC and para-cancerous samples via bioinformatic analysis. Kaplan-Meier survival analysis revealed that MS4A1 and TNFRSF17 were associated with the overall survival of patients with CC. Cellular experiments were performed for verification, and the protein expression of target genes was determined via immunohistochemical staining of CC and the adjacent healthy tissues. The proliferation, migration and invasion abilities of CC cells with high expression of target genes were determined via in vitro experiments.

Results: Differential gene expression, weighted gene co-expression and survival analyses revealed that patients with CC with high expression of MS4A1 and TNFRSF17 had longer overall survival. The expression of these two genes was lower in CC tissues than in healthy colon tissues and was remarkably associated with the infiltration of various immune cells, including CD8+ T cells, in the tumour microenvironment (TME) of CC. Patients with CC with high expression of MS4A1 and TNFRSF17 were more sensitive to immunotherapy. Quantitative reverse transcription-polymerase chain reaction, western blotting and immunohistochemical staining validated the differential expression of MS4A1 and TNFRSF17. In addition, Cell Counting Kit-8, wound healing and transwell assays revealed that the proliferation, migration and invasion abilities of CC cells were weakened after overexpression of MS4A1 and TNFRSF17.

Conclusions: The core genes MS4A1 and TNFRSF17 can be used as markers to predict the sensitivity of patients with CC to immunotherapy and have potential applications in gene therapy to inhibit CC progression.

Keywords: CD8+ T cell; MS4A1; TNFRSF17; colon cancer; prognostic marker.