由于T细胞浸润不足，肿瘤逃避了免疫监视。 CD8 + T细胞在乳腺癌中的增加表明对免疫疗法有满意的反应。虽然已经确认COPS6为一个癌基因，但其在调节抗肿瘤免疫反应方面的作用尚未被定义。在这项研究中，我们调查了COPS6对体内肿瘤免疫逃逸的影响。在C57BL / 6J小鼠和BALB / c裸鼠中建立了肿瘤移植模型。进行流式细胞术以鉴定COPS6对肿瘤浸润的CD8 + T细胞的作用。通过分析TCGA和GTEx队列，我们发现COPS6表达在各种癌症中显着上调。在人骨肉瘤细胞系U2OS和非小细胞肺癌细胞系H1299中，我们展示了p53负调控COPS6启动子活性。在人乳腺癌MCF-7细胞中，COPS6过表达刺激了p-AKT表达以及肿瘤细胞的增殖和恶性转化，而COPS6的沉默导致了相反的效果。COPS6的沉默也明显抑制了BALB / c裸鼠带有小鼠乳腺癌EMT6异种移植体的生长。生物信息学分析表明，COPS6是肿瘤微环境中IL-6产生的介质，也是乳腺癌中CD8 + T细胞肿瘤浸润的负调控因子。在C57BL6小鼠体内携带EMT6异种移植体时，COPS6在EMT6细胞中的沉默增加了肿瘤浸润的CD8 + T细胞的数量，而在COPS6KD EMT6细胞中IL-6的沉默则减少了肿瘤浸润的CD8 + T细胞。我们得出结论，COPS6通过调节IL-6分泌减少CD8 + T细胞的浸润和功能而促进乳腺癌进展。这项研究阐明了p53 / COPS6 / IL-6 / CD8 + 肿瘤浸润淋巴细胞信号在乳腺癌进展和免疫逃逸中的作用，开辟了一条新的道路，以开发针对COPS6的治疗方法，以增强肿瘤免疫原性并治疗免疫“冷”乳腺癌。©2023.该作者（们）独家许可中国科学院上海药物研究所和中国药理学会。

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.© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.