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COPS6 promotes tumor progression and reduces CD8+ T cell infiltration by repressing IL-6 production to facilitate tumor immune evasion in breast cancer

Acta Pharmacologica Sinica volume 44, pages 1890–1905 (2023)Cite this article

Abstract

Due to poor T cell infiltration, tumors evade immune surveillance. Increased CD8+ T cell infiltration in breast cancer suggests a satisfactory response to immunotherapy. COPS6 has been identified as an oncogene, but its role in regulating antitumor immune responses has not been defined. In this study, we investigated the impact of COPS6 on tumor immune evasion in vivo. Tumor transplantation models were established in C57BL/6 J mice and BALB/c nude mice. Flow cytometry was conducted to identify the role of COPS6 on tumor-infiltrating CD8+ T cells. By analyzing the TCGA and GTEx cohort, we found that COPS6 expression was significantly up-regulated in a variety of cancers. In human osteosarcoma cell line U2OS and non-small cell lung cancer cell line H1299, we showed that p53 negatively regulated COPS6 promoter activity. In human breast cancer MCF-7 cells, COPS6 overexpression stimulated p-AKT expression as well as the proliferation and malignant transformation of tumor cells, whereas knockdown of COPS6 caused opposite effects. Knockdown of COPS6 also significantly suppressed the growth of mouse mammary cancer EMT6 xenografts in BALB/c nude mice. Bioinformatics analysis suggested that COPS6 was a mediator of IL-6 production in the tumor microenvironment and a negative regulator of CD8+ T cell tumor infiltration in breast cancer. In C57BL6 mice bearing EMT6 xenografts, COPS6 knockdown in the EMT6 cells increased the number of tumor-infiltrating CD8+ T cells, while knockdown of IL-6 in COPS6KD EMT6 cells diminished tumor infiltrating CD8+ T cells. We conclude that COPS6 promotes breast cancer progression by reducing CD8+ T cell infiltration and function via the regulation of IL-6 secretion. This study clarifies the role of p53/COPS6/IL-6/CD8+ tumor infiltrating lymphocytes signaling in breast cancer progression and immune evasion, opening a new path for development of COPS6-targeting therapies to enhance tumor immunogenicity and treat immunologically “cold” breast cancer.

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Fig. 1: The expression level of COPS6 in various types of tumor and normal tissues.
Fig. 2: p53 negatively regulates COPS6 promoter activity.
Fig. 3: Highly expressed COPS6 predicts a poor prognosis in breast cancer and correlates with an immunosuppressive tumor microenvironment.
Fig. 4: COPS6 promoted breast cancer progression.
Fig. 5: COPS6 inhibits the IL-6 production in breast cancer.
Fig. 6: IL-6 positively regulates CD8+ T cells in breast cancer.
Fig. 7: COPS6 inhibits CD8+ T cell infiltration via IL-6 production in breast cancer.
Fig. 8: Model of COPS6-mediated immunosuppressive effect in breast cancer.

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Acknowledgements

This work was supported by the Graduate Student Scientific Research Innovation Projects in Jiangsu Province (KYCX22-2944) and Xuzhou Key Research and Development Projects (KC22119).

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  1. These authors contributed equally: Wen-qi Du, Zhi-man Zhu, Xin Jiang

Authors and Affiliations

  1. Department of Pathology, Xuzhou Medical University, Xuzhou, 221004, China

    Wen-qi Du, Zhi-man Zhu, Xin Jiang, Meng-jie Kang & Dong-sheng Pei

  2. Department of Human Anatomy, Xuzhou Medical University, Xuzhou, 221004, China

    Wen-qi Du

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DSP designed the study; WQD and ZMZ performed the Research; XJ and MJK analyzed the data; WQD, ZMZ, and XJ wrote the paper.

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Correspondence to Dong-sheng Pei.

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Du, Wq., Zhu, Zm., Jiang, X. et al. COPS6 promotes tumor progression and reduces CD8+ T cell infiltration by repressing IL-6 production to facilitate tumor immune evasion in breast cancer. Acta Pharmacol Sin 44, 1890–1905 (2023). https://doi.org/10.1038/s41401-023-01085-8

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