Dual TGF-β and PD-1 blockade synergistically enhances MAGE-A3-specific CD8+ T cell response in esophageal squamous cell carcinoma
Dual TGF-β and PD-1 blockade synergistically enhances MAGE-A3-specific CD8+ T cell response in esophageal squamous cell carcinoma
复制标题
TGF-β 和 PD-1 双重阻断可协同增强食管鳞状细胞癌中 MAGE-A3 特异性 CD8(+) T 细胞反应。
DOI：
10.1002/ijc.31730
复制
发表时间：
2018-11-15
影响因子：
6.4
通讯作者：
Zhang, Yi
中科院分区：
文献类型：
--
作者：
Chen, Xinfeng;Wang, Liping;Zhang, Yi
PD-1在肿瘤浸润的抗原特异性T细胞上高表达，限制其抗肿瘤功能。阻断PD-1/PD-L1信号传导在晚期癌症患者中显示出前所未有的疗效。然而，只有有限的患者从这种疗法中受益。我们的研究旨在探讨mage - a3特异性CD8(+) T细胞在食管鳞状细胞癌（ESCC）患者中的生物学特性、功能调控和逆转。评估肿瘤微环境（TME）中mage - a3特异性CD8(+) T细胞功能缺失和恢复的基本原理。MAGE-A3特异性CD8(+) T细胞能溶解HLA-A2(+)/MAGE-A3（+）肿瘤细胞。四聚体（+）T细胞频率在老年患者中较高，而在淋巴结转移和肿瘤晚期患者中较低（p < 0.05）。在Cox回归分析中，CD107a（高）在功能性T细胞上的表达是一个独立的预后因素。PD-1在功能失调的抗原特异性CD8(+) T细胞和肿瘤浸润T淋巴细胞上高表达（p < 0.05）。骨髓源性抑制细胞（MDSCs）衍生的tgf - β介导的PD-1在CD8(+) T细胞上的高表达，导致TME患者对PD-1/PD-L1阻断具有抗性。体外/体内实验表明，双重阻断PD-1/PD-L1和tgf - β信号通路可协同恢复抗原特异性CD8(+) T细胞的功能和抗肿瘤能力。功能性mage - a3特异性CD8(+) T细胞的存在对ESCC患者的生存具有独立的预后影响。此外，mdscs衍生的tgf - β增加了T细胞上PD-1的表达，降低了对PD-1/PD-L1阻断的敏感性。结合T细胞治疗与双重PD-1/PD-L1和tgf - β信号通路阻断可以被认为是一种有前途的癌症治疗策略。
PD-1 is highly expressed on tumor-infiltrated antigen-specific T cells and limit the antitumor function. Blocking of PD-1/PD-L1 signaling has shown unprecedented curative efficacies in patients with advanced cancer. However, only a limited population of patients benefited from such therapies. Our study aimed to explore biological properties, functional regulation and reversal of MAGE-A3-specific CD8(+) T cells in patients with esophageal squamous cell carcinoma (ESCC). The underlying principle of deficiency and restoring MAGE-A3-specific CD8(+) T cells function in tumor microenvironment (TME) was evaluated. MAGE-A3-specific CD8(+) T cells could lyse HLA-A2(+)/MAGE-A3(+) tumor cells. Tetramer(+) T cell frequency was higher in elder patients, but lower in patients with lymph node metastasis and late tumor stage (p < 0.05). CD107a(high) expression on functional T cells was an independent prognostic factor in Cox regression analysis. PD-1 was highly expressed on dysfunctional antigen-specific CD8(+) T cells and tumor infiltrating T lymphocytes (p < 0.05). Myeloid-derived suppressor cells (MDSCs) derived-TGF-beta mediated PD-1(high) expression on CD8(+) T cells, which led to be resistance to PD-1/PD-L1 blockade in TME. Dual PD-1/PD-L1 and TGF-beta signaling pathway blockades synergistically restored the function and antitumor ability of antigen-specific CD8(+) T cells in vitro/vivo assay. The presence of functional MAGE-A3-specific CD8(+) T cells had an independent prognostic impact on survival of patients with ESCC. Furthermore, MDSCs-derived TGF-beta increased PD-1 expression on T cells and decreased the sensitivity to PD-1/PD-L1 blockade. Combining T cell-based therapy with dual PD-1/PD-L1 and TGF-beta signaling pathway blockade could be considered a promising strategy for cancer treatment.