Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2022-05-31 , DOI: 10.1007/s10565-022-09722-4 Zhao-Ying Yang 1 , Wen-Long Zhang 2 , Cheng-Wei Jiang 3 , Guang Sun 1
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Loss of expression or protein kinase B (Akt1)-mediated post-translational modification of the RNA binding protein Poly r(C) binding protein 1 (PCBP1) is closely related to metastatic advancement of breast cancer. However, the role of PCBP1 in tumorigenesis is not completely defined. Using a xenograft orthotopic model of breast tumorigenesis (4T1-Pcbp1−/−), we show here that PCBP1 knockdown-induced tumorigenesis is inhibited by activation of the WNT signaling via treating with the glycogen synthase kinase 3 beta inhibitor TWS119, but not the Akt2/Akt3 inhibitor GSK690693. Mass cytometry-based evaluation of the tumor microenvironment (TME) revealed significantly more regulatory T cells (Tregs) and significantly less cytotoxic T cells in 4T1-Pcbp1−/−mice treated with saline control in comparison to mice treated with TWS119. Infiltrating cytotoxic T cells were phenotypically and functionally exhausted. Treatment with TWS119 resulted in rescue of cytotoxic T cell function and inhibition of suppressor activity of Tregs. Using cytotoxic T cells isolated from healthy donors, we show that TWS119-induced WNT signaling-mediated inhibition of cytotoxic T cell expansion is reliant on expression of PCBP1. In conclusion, decreased PCBP1 expression favors breast tumorigenesis by potentiating skewing of tumor infiltrating T cells towards Tregs, thereby effectively suppressing anti-tumor immunity.
Graphical abstract
中文翻译：
PCBP1 介导的 WNT 信号传导调节对于乳腺肿瘤发生至关重要
RNA 结合蛋白 Poly r(C) 结合蛋白 1 (PCBP1) 的表达缺失或蛋白激酶 B (Akt1) 介导的翻译后修饰与乳腺癌的转移进展密切相关。然而，PCBP1 在肿瘤发生中的作用尚未完全明确。使用乳腺肿瘤发生的异种移植原位模型 (4T1- Pcbp1 −/− )，我们在此表明，通过用糖原合酶激酶 3 β 抑制剂 TWS119 治疗，而不是 Akt2 治疗，激活 WNT 信号传导，可抑制 PCBP1 敲低诱导的肿瘤发生。 /Akt3 抑制剂 GSK690693。基于质量流式细胞仪的肿瘤微环境 (TME) 评估显示，与 TWS119 治疗的小鼠相比，用盐水对照治疗的4T1- Pcbp1 −/−小鼠中调节性 T 细胞 (Treg) 显着增多，细胞毒性 T 细胞显着减少。浸润性细胞毒性 T 细胞在表型和功能上均已耗尽。TWS119 治疗可挽救细胞毒性 T 细胞功能并抑制 Tregs 的抑制活性。使用从健康供体中分离的细胞毒性 T 细胞，我们发现 TWS119 诱导的 WNT 信号介导的细胞毒性 T 细胞扩增抑制依赖于 PCBP1 的表达。总之，PCBP1表达减少通过增强肿瘤浸润T细胞向T细胞的偏向而有利于乳腺肿瘤的发生，从而有效抑制抗肿瘤免疫。
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