肿瘤细胞治疗研究
英文原题：DUSP4 promotes anti-tumor CD8(+) T cell function and boosts CAR-T cell efficacy in mouse colorectal cancer.
我们的数据表明，DUSP4 支持 CD8⁺ T 细胞的细胞毒性功能，并提示 DUSP4 可能是增强抗肿瘤免疫的有前景的治疗靶点。
CD8⁺ T 细胞在抗肿瘤免疫中发挥核心作用，其活化与功能受到细胞外及细胞内信号通路的严格调控。包括 DUSP4 在内的双特异性磷酸酶（DUSP）可使蛋白质的丝氨酸/苏氨酸及酪氨酸残基去磷酸化，从而调节细胞信号。本研究探讨 DUSP4 在肿瘤免疫中的作用。结直肠癌（CRC）组织中 DUSP4 表达较低的患者，生存期短于表达较高者。相反，在 AOM/DSS 诱导的雄性小鼠 CRC 模型中，全身性 DUSP4 缺失会促进肿瘤发生，并削弱 CD8⁺ T 细胞介导的抗肿瘤免疫。从机制上看，敲除 DUSP4 会增加 ERK2 介导的 T 细胞活化调节因子 Klf2 表达，进而抑制 KLF2 介导的细胞毒性程序。在 CD19⁺ CRC 异种移植小鼠模型中，CRISPRa 介导的 DUSP4 激活促进抗 CD19 CAR-T 细胞增殖并增强其抗肿瘤细胞毒性。综上，DUSP4 有助于维持 CD8⁺ T 细胞的细胞毒功能，并可能成为增强抗肿瘤免疫的治疗靶点。
The activation and function of CD8 + T cells, which are central for anti-tumor immunity, are tightly regulated by extracellular and intracellular signaling pathways. Dual-specificity phosphatases (DUSP), including DUSP4, dephosphorylate serine/threonine and tyrosine residues of proteins to modulate cellular signaling. Here, we investigate the role of DUSP4 in cancer immunity. Patients with colorectal cancers (CRC) with lower DUSP4 expression across the CRC tissue exhibit shorter survival compared to those with higher DUSP4 expression. By contrast, in AOM/DSS-induced male mouse CRC models, global DUSP4 deficiency enhances tumorigenesis and compromises CD8 + T cell-mediated anti-tumor immunity. Mechanistically, DUSP4 knockout increases ERK2-mediated expression of the T cell activation regulator Klf2, thereby suppressing KLF2-mediated cytotoxic programs. In a CD19 + CRC xenograft mouse model, CRISPRa-mediated DUSP4 activation promotes anti-CD19 CAR-T cell proliferation and anti-tumor cytotoxicity. Thus, our data show that DUSP4 supports CD8 + T cell cytotoxic functions and suggest that DUSP4 may be a promising therapeutic target for enhancing anti-tumor immunity.
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