Nuclear Aurora kinase A triggers programmed death-ligand 1-mediated immune suppression by activating MYC transcription in triple-negative breast cancer

Cancer Communications

article

Shulan Sun¹  Wei Zhou¹  Xiaoxi Li¹  Fei Peng¹  Min Yan⁴  Yajing Zhan¹  Fan An¹  Xiaoyan Li⁵  Yunyong Liu⁶  Quentin Liu¹  Haozhe Piao¹ 

[1] Central Laboratory, Cancer Hospital of China Medical University, Dalian Medical University Clinical Oncology College, Liaoning Cancer Hospital & Institute;These authors contributed equally to this work;Institute of Cancer Stem Cell, Dalian Medical University;State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center;Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and institute;Department of Cancer Prevention and Treatment, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute;Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute

关键词: Aurora kinase A;    immune evasion;    immunotherapy;    MYC;    programmed death-ligand 1;    triple-negative breast cancer;   

DOI  :  10.1002/cac2.12190

学科分类：社会科学、人文和艺术（综合）

来源: Springer

【 摘 要 】

Background Increasing studies have reported that oncogenes regulate components of the immune system, suggesting that this is a mechanism for tumorigenesis. Aurora kinase A (AURKA), a serine/threonine kinase, is involved in cell mitosis and is essential for tumor cell proliferation, metastasis, and drug resistance. However, the mechanism by which AURKA is involved in immune response regulation is unclear. Therefore, this study aimed to investigate the role of AURKA in immune regulation in triple-negative breast cancer (TNBC). Methods Peripheral blood mononuclear cells (PBMCs) were co-cultured with TNBC cells. The xCELLigence Real-Time Cell Analyzer-MP system was used to detect the killing efficiency of immune cells on TNBC cells. The expression of immune effector molecules was tested by quantitative real-time polymerase chain reaction (qRT-PCR) to evaluate immune function. Furthermore, to validate AURKA-regulated immune response in vivo, 4T1 murine breast cancer cell line with AURKA overexpression or downregulation was engrafted into BALB/c mice. The distribution and proportion of immune cells in tumors were further evaluated by immunohistochemistry and flow cytometry. Results Downregulation of AURKA in TNBC cells increased immune response by activating CD8 + T cell proliferation and activity. Nuclear rather than cytoplasmic AURKA-derived programmed death-ligand 1 (PD-L1) expression was independent of its kinase activity. Mechanistic investigations showed that nuclear AURKA increased PD-L1 expression via an MYC-dependent pathway. PD-L1 overexpression mostly reversed AURKA silencing-induced expression of immune effector molecules, including interleukin- (IL-2), interferon-γ (IFN-γ), and perforin. Moreover, AURKA expression was negatively correlated with the enrichment and activity of tumor-infiltrating CD8 + T cells in 4T1 engrafted BALB/c mouse model. Conclusions Nuclear AURKA elevated PD-L1 expression via an MYC-dependent pathway and contributed to immune evasion in TNBC. Therapies targeting nuclear AURKA may restore immune responses against tumors.

【 授权许可】

CC BY|CC BY-NC-ND