Modulation of CD8(+) memory stem T cell activity and glycogen synthase kinase 3β inhibition enhances anti-tumoral immunity in gastric cancer.
Modulation of CD8(+) memory stem T cell activity and glycogen synthase kinase 3β inhibition enhances anti-tumoral immunity in gastric cancer.
复制标题
调节 CD8( ) 记忆干 T 细胞活性和糖原合酶激酶 3 β 抑制可增强胃癌的抗肿瘤免疫
DOI：
10.1080/2162402x.2017.1412900
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Zhuang Y
中科院分区：
文献类型：
--
作者：
Zhang JY;Zhao YL;Lv YP;Cheng P;Chen W;Duan M;Teng YS;Wang TT;Peng LS;Mao FY;Liu YG;Fu XL;Yu PW;Luo P;Zhang WJ;Zou QM;Zhuang Y
CD8+记忆干细胞在胃癌的抗肿瘤免疫和免疫治疗反应中的潜在作用尚未得到证实。我们发现与健康人相比，胃癌患者外周血中CD8+记忆干细胞T细胞的频率升高，并随着疾病的进展而下降。尽管体外细胞毒活性很低，但与CD8+中心型或效应型记忆T细胞相比，过继转移CD8+记忆干细胞到RAG1−/−荷瘤小鼠可促进肿瘤消退。这种效应与脾、引流淋巴结和肿瘤浸润性CD8+T细胞数量的增加以及动态平衡期间未见的CD8+T细胞表型改变有关。已知抑制GSK-3β可以通过抑制体内效应T细胞的分化来促进记忆干细胞的积聚。然而，令人惊讶的是，抑制GSK-3β在体外反过来增加了CD8+记忆干细胞的细胞毒能力，这与诱导包括Fas L在内的效应T细胞相关效应蛋白有关。最后，抑制GSK-3β后的FasL中和直接减弱了CD8+记忆干细胞在体外和体内的抗肿瘤能力。综上所述，我们的发现确定了调节CD8+记忆干细胞的治疗潜力，以改善对胃癌的抗肿瘤反应。
The potential contributions of CD8+ memory stem T cells to anti-tumor immunity and immunotherapy responses in gastric cancer has not been demonstrated. We found that CD8+ memory stem T cell frequencies were increased in the peripheral blood of gastric cancer patients compared to healthy donors and declined in frequency with disease progression. Despite minimal in vitro cytotoxic activity, the adoptive transfer of CD8+ memory stem T cells into Rag1−/− tumor bearing mice enhanced tumor regression compared to CD8+ central or effector memory T cell counterparts. This effect was associated with an increase in splenic, draining lymph node and tumor infiltrating CD8+ T cell numbers and the development of an altered CD8+ T cell phenotype not seen during homeostasis. GSK-3β inhibition is known to promote memory stem T cell accumulation by arresting effector T cell differentiation in vivo. Surprisingly however, GSK-3β inhibition conversely increased the cytotoxic capacity of CD8+ memory stem T cells in vitro, and this was associated with the induction of effector T cell-associated effector proteins including FasL. Finally, FasL neutralization following GSK-3β inhibition directly attenuated the anti-tumoral capacity of CD8+ memory stem T cells both in vitro and in vivo. Altogether, our findings identify the therapeutic potential of modulating CD8+ memory stem T cells for improved anti-tumoral responses against gastric cancer.