MMP9 Expression Correlates With Cisplatin Resistance in Small Cell Lung Cancer Patients

Longqiu Wu; Xiangcai Wang; Xin He; Qiang Li; Qian Hua; Rongrong Liu; Zhengang Qiu

doi:10.3389/fphar.2022.868203

MMP9 Expression Correlates With Cisplatin Resistance in Small Cell Lung Cancer Patients

Front Pharmacol. 2022 Apr 1:13:868203. doi: 10.3389/fphar.2022.868203. eCollection 2022.

Authors

Longqiu Wu¹, Xiangcai Wang¹, Xin He¹, Qiang Li¹, Qian Hua¹, Rongrong Liu^{2

3}, Zhengang Qiu¹

Affiliations

¹ Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
² Department of Neurology, Ganzhou People's Hospital, Ganzhou, China.
³ Department of Neurology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China.

Abstract

Background: Cisplatin is the basis of the primary treatment for SCLC chemotherapy. However, the limited objective response rate and definite drug resistance greatly restrict the clinical potential and therapeutic benefits of cisplatin use. Therefore, it is essential to identify biomarkers that can discern the sensitivity of SCLC patients to cisplatin treatment. Methods: We collected two SCLC cohorts treated with cisplatin that included mutation data, prognosis data and expression data. The sensitivity of cisplatin was evaluated by the pRRophetic algorithm. MCPcounter, quanTIseq, and xCell algorithms were used to evaluate immune cell score. GSEA and ssGSEA algorithms were used to calculate immune-related pathway scores. Univariate and multivariate Cox regression models were employed, and survival analysis was used to evaluate the prognostic value of the candidate genes. Results: MMP9-High is related to improved clinical prognoses of patients with SCLC (HR = 0.425, p = 0.0085; HR = 0.365, p = 0.0219). Multivariate results showed that MMP-High could be used as an independent predictor of the prognosis of SCLC after cisplatin treatment (HR = 0.216, p = 0.00153; HR = 0.352; p = 0.0199). In addition, MMP9-High displayed a significantly lower IC50 value of cisplatin and higher immunogenicity than MMP9-Low SCLC. Compared with MMP9-Low SCLC, MMP9-High included significantly increased levels of T-cells, cytoxic lymphocytes, B-cells, NK-cells, and dense cells (DCS). Similarly, the activity of cytokine binding, B-cell, NK-cell mediated immune response chemokine binding, and antigen presentation pathways in MMP9-High was significantly higher than that in MMP9-Low. Conclusion: In this study, we identified that MMP9-High could be potentially considered a novel biomarker used to ascertain the improved prognosis of SCLC patients after cisplatin treatment. Furthermore, we indicated that the tumor immune microenvironment of MMP9-High SCLC is mainly characterized by a large number of infiltrated activated immune cells as well as activated immune-related pathways.

Keywords: MMP9; cisplatin; resistance; small lung cell cancer; survival.