Identification of MAP3K15 as a potential prognostic biomarker and correlation with immune infiltrates in osteosarcoma

Zhuning Chen; Haoran Kong; Zhaopeng Cai; Keng Chen; Boyang Wu; Haonan Li; Peng Wang; Yanfeng Wu; Huiyong Shen

doi:10.21037/atm-21-3181

Identification of MAP3K15 as a potential prognostic biomarker and correlation with immune infiltrates in osteosarcoma

Ann Transl Med. 2021 Jul;9(14):1179. doi: 10.21037/atm-21-3181.

Authors

Zhuning Chen^{1

2}, Haoran Kong¹, Zhaopeng Cai², Keng Chen², Boyang Wu², Haonan Li², Peng Wang², Yanfeng Wu³, Huiyong Shen^{1

2}

Affiliations

¹ Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
² Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
³ Center for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.

Abstract

Background: Osteosarcoma (OS) is a type of primary malignant tumor, and increasing evidence shows the clinical benefits of immunotherapy in treating OS. However, the lack of comprehensive studies on the complex OS immune microenvironment hinders the application of immunotherapy. Thus, this study aimed to systematically explore the immune characteristics of OS and identify novel biomarkers for OS treatment.

Methods: We systematically studied the immune score and proportions of infiltrating immune cells in OS in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases using the ESTIMATE and CIBERSORT algorithms. Differential expression and functional analyses were used to identify dysregulated genes and explore their functions. Survival and Cox regression analyses were applied to establish an immune-related prognostic signature. Additionally, qPCR and immunohistochemistry were performed to validate the results.

Results: A total of 103 differentially expressed immune genes (DEIGs) were found in the TARGET-OS and GSE39058 databases, and these DEIGs were mainly enriched in leukocyte proliferation, leukocyte differentiation, osteoclast differentiation, natural killer (NK) cell-mediated cytotoxicity, and the adaptive immune system. A predictive signature was constructed based on the survival analysis, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.65. Moreover, we found that mitogen-activated protein kinase kinase kinase 15 (MAP3K15) can predict the prognosis of patients with OS and is closely related to CD4⁺ T cells and macrophages. The OS patients with high MAP3K15 expression had a significantly poorer prognosis.

Conclusions: Our study found that MAP3K15, whose expression level is closely related to immune activity in tumors, is a critical immune-related biomarker, and our findings may provide a basis for OS immunotherapy.

Keywords: Mitogen-activated protein kinase kinase kinase 15 (MAP3K15); bioinformatics; immune infiltrates; osteosarcoma (OS); prognosis.