CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题:Two chemotherapeutic agents expand stem-like CD62L(+)CD8(+) T cells in antitumor immune responses.
Two chemotherapeutic agents expand stem-like CD62L(+)CD8(+) T cells in antitumor immune responses.
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本研究表明,DAC 和 5-FU 均促进了 TdLNs 中干细胞样 CD8+ T TSM 细胞的分化,并显著增强了肿瘤微环境中干细胞样 CD62L+ CD8+ Tpex 和 CX3CR1+ Tex int 细胞的分化与扩增。Eomes 的敲除部分影响了 DAC 促进干细胞样 CD8+ T 细胞分化与扩增的作用。
近期研究发现,耗竭性 CD8+ T 细胞(CD8+ Tpex)的前体细胞在肿瘤免疫中具有干细胞样特征,其来源于肿瘤引流淋巴结(TdLN)衍生的肿瘤特异性记忆(CD8+ T TSM)细胞。这两个 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,并能增殖和分化为短暂效应样耗竭 T 细胞(Tex int)。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应答;然而,化疗药物是否增加这两种干细胞样 CD8+ T 细胞仍有待进一步探索。
通过单细胞测序数据分析了人结直肠肿瘤中与Tpex细胞相关的亚群。构建了野生型和Eomes条件性敲除小鼠的CT26和B16肿瘤模型,并在地西他滨(DAC)、多柔比星(DOX)和5-氟尿嘧啶(5-FU)处理后,通过流式细胞术剖析了小鼠中T TSM、Tpex和Tex亚群的变化。
在本研究中,我们证明了DAC和5-FU在TdLNs中扩增了CD8+ T TSM细胞。同时,我们验证了DAC和5-FU显著促进了CD62L+ CD8+ Tpex细胞的扩增,并随后增强了CX3CR1+ CD8+ Tex int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扩增的这种CD8+ T亚群没有影响。
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 TSM , Tpex and Tex subsets in mice were dissected by flow cytometry after treatment with decitabine (DAC), doxorubicin (DOX) and 5-Fluorouracil (5-FU).
In this study, we demonstrated that DAC and 5-FU expanded CD8 + T TSM cells in TdLNs. At the same time, we validated that DAC and 5-FU substantially promoted the expansion of CD62L + CD8 + Tpex cells and subsequently increased effector function of CX3CR1 + CD8 + Tex int 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.
The present study demonstrated that both DAC and 5-FU promoted the differentiation of stem-like CD8 + T TSM cells in TdLNs and significantly enhanced the differentiation and expansion of stem-like CD62L + CD8 + Tpex and CX3CR1 + Tex int 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.
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