Chen Yu-Li, Lin Han-Wei, Sun Nai-Yun, Yie Jr-Chi, Hung Hsueh-Chih, Chen Chi-An, Sun Wei-Zen, Cheng Wen-Fang
Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei City 100, Taiwan.
Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City 100, Taiwan.
Cancers (Basel). 2019 May 2;11(5):617. doi: 10.3390/cancers11050617.
The life span of dendritic cells (DCs) can become short following induced activation, which is associated with metabolic transition due to the regulation of mechanistic target of rapamycin (mTOR). The purpose of this study was to investigate the potential of inhibiting mTOR to modulate DC functions for elevating the anti-tumor effects of DNA vaccines. Therefore, the influences of various inhibitors of mTOR (mTORi) on the expressions of DC maturation markers, the abilities of antigen presenting and processing of BMM-derived DCs and the tumor killing effects of E7-specific CD8 T lymphocytes activated by BMM-derived DCs were in vitro examined. The anti-tumor effects of connective tissue growth factor (CTGF)/E7 DNA vaccine and/or mTORi were also in vivo analyzed. In our study, suppressive effects of mTORi on the DC maturation markers expressed on BMMCs could be reversed. The mTORi-treated mature BMM-derived DCs tended to be non-apoptotic. These mTORi-treated BMM-derived DCs could have better antigen presenting and processing abilities. The E7-specific cytotoxic CD8+ T lymphocytes could have more potent tumoricidal activity following activation of mTORi-treated BMM-derived DCs. For tumor-bearing mice, those treated with CTGF/E7 DNA vaccine and mTORi indeed can have higher percentages of mature DCs in the TME, better disease control and longer survivals. Consequently, application of mTORi can be a pharmacological approach for temporally increasing life span, antigen presenting and antigen processing of DCs to strengthen the therapeutic outcome of cancer immunotherapy.
树突状细胞（DCs）在诱导激活后寿命可能会缩短，这与雷帕霉素机制性靶标（mTOR）调控导致的代谢转变有关。本研究的目的是探讨抑制mTOR调节DC功能以提高DNA疫苗抗肿瘤效果的潜力。因此，体外检测了各种mTOR抑制剂（mTORi）对DC成熟标志物表达、骨髓来源的DCs抗原呈递和加工能力以及骨髓来源的DCs激活的E7特异性CD8 T淋巴细胞的肿瘤杀伤作用的影响。还在体内分析了结缔组织生长因子（CTGF）/E7 DNA疫苗和/或mTORi的抗肿瘤作用。在我们的研究中，mTORi对骨髓肥大细胞上表达的DC成熟标志物的抑制作用可以被逆转。经mTORi处理的成熟骨髓来源的DCs倾向于不凋亡。这些经mTORi处理的骨髓来源的DCs具有更好的抗原呈递和加工能力。经mTORi处理的骨髓来源 的DCs激活后，E7特异性细胞毒性CD8+ T淋巴细胞具有更强的杀瘤活性。对于荷瘤小鼠，用CTGF/E7 DNA疫苗和mTORi治疗的小鼠在肿瘤微环境中确实可以有更高比例的成熟DCs，更好地控制疾病并延长生存期。因此，应用mTORi可以作为一种药理学方法，暂时延长DCs的寿命、抗原呈递和抗原加工能力，以加强癌症免疫治疗的疗效。
