两种化疗药物在抗肿瘤免疫反应中可扩增干细胞样CD62L⁻CD8⁺ T细胞。
Two chemotherapeutic agents expand stem-like CD62LCD8 T cells in antitumor immune responses.
作者信息
Ruan Xiaokang, Wu Linwei, Tang Zijian, Li Yao, Wang Jin, Jiang Haolin, Zhang Li, Wang Shengjia, Chen Zhaoqiang, Yuan Chenlei, Xia Yujian, Pan Yan, Gao Jianling, Zhao Xin
机构信息
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
Department of General Surgery, People's Hospital of Dongxihu District, Wuhan, China.
出版信息
Front Immunol. 2025 Apr 1;16:1533857. doi: 10.3389/fimmu.2025.1533857. eCollection 2025.
INTRODUCTION
Recent findings reveal that the precursors of exhausted CD8 T (CD8 Tpex) cells possess stem-like signatures in tumor immunity, which originate from tumor draining lymph node (TdLN)-derived tumor-specific memory (CD8 T) cells. Both of these T subsets can be collectively referred to as stem-like CD8 T cells, which demonstrate robust self-renewal ability and can proliferate and differentiate into transitory effector-like exhausted T cells (Tex). There are reports that chemotherapeutic drugs can promote the antitumor immune responses of patients by increasing the number of CD8 T cells; however, whether chemotherapeutic drugs increase these two stem-like CD8 T cells remain further exploration.
METHODS
Tpex cell-associated subpopulations in human colorectal tumors were analyzed by using single-cell sequencing data. CT26 and B16 tumor models of wild type and Eomes conditional knockout mice were constructed, and the changes of T, Tpex and Tex subsets in mice were dissected by flow cytometry after treatment with decitabine (DAC), doxorubicin (DOX) and 5-Fluorouracil (5-FU).
RESULTS
In this study, we demonstrated that DAC and 5-FU expanded CD8 T cells in TdLNs. At the same time, we validated that DAC and 5-FU substantially promoted the expansion of CD62LCD8 Tpex cells and subsequently increased effector function of CX3CR1 CD8 Tex cells. In addition, the conditional knockout of transcription factor Eomes in CD8 T cells partially eliminated DAC-amplified CD62L CD8 Tpex cells, but had no effect on such CD8 T subset expanded by 5-FU.
CONCLUSION
The present study demonstrated that both DAC and 5-FU promoted the differentiation of stem-like CD8 T cells in TdLNs and significantly enhanced the differentiation and expansion of stem-like CD62L CD8 Tpex and CX3CR1 Tex cells in tumor microenvironment. The knockout of Eomes partially influenced the role of DAC in promoting the differentiation and expansion of stem-like CD8 T cells.
引言
最近的研究发现表明，耗竭性CD8 T细胞（CD8 Tpex）的前体在肿瘤免疫中具有干细胞样特征，其起源于肿瘤引流淋巴结（TdLN）衍生的肿瘤特异性记忆（CD8 T）细胞。这两种T细胞亚群可统称为干细胞样CD8 T细胞，它们表现出强大的自我更新能力，能够增殖并分化为短暂的效应样耗竭T细胞（Tex）。有报道称化疗药物可通过增加CD8 T细胞数量来促进患者的抗肿瘤免疫反应；然而，化疗药物是否能增加这两种干细胞样CD8 T细胞仍有待进一步探索。
方法
利用单细胞测序数据分析人类结直肠癌肿瘤中与Tpex细胞相关的亚群。构建野生型和Eomes条件性敲除小鼠的CT26和B16肿瘤模型，在用地西他滨（DAC）、阿霉素（DOX）和5-氟尿嘧啶（5-FU）治疗后，通过流式细胞术分析小鼠中T、Tpex和Tex亚群的变化。
结果
在本研究中，我们证明DAC和5-FU可使TdLNs中的CD8 T细胞扩增。同时，我们证实DAC和5-FU可显著促进CD62L⁺CD8 Tpex细胞的扩增，并随后增强CX3CR1⁺CD8 Tex细胞的效应功能。此外，CD8 T细胞中转录因子Eomes的条件性敲除部分消除了DAC扩增的CD62L⁺CD8 Tpex细胞，但对5-FU扩增的此类CD8 T亚群没有影响。
结论
本研究表明，DAC和5-FU均可促进TdLNs中干细胞样CD8 T细胞的分化，并显著增强肿瘤微环境中干细胞样CD62L⁺CD8 Tpex和CX3CR1⁺Tex细胞的分化和扩增。Eomes的敲除部分影响了DAC在促进干细胞样CD8 T细胞分化和扩增中的作用。
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