Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China.
Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China.
J Leukoc Biol. 2021 Aug;110(2):315-325. doi: 10.1002/JLB.5MA1120-776RR. Epub 2021 Apr 28.
Natural killer (NK) cells have a great potential in cancer immunotherapy. However, their therapeutic efficacy is clinically limited owing to cancer cell immune escape. Therefore, it is urgently necessary to develop novel method to improve the antitumor immunity of NK cells. In the present study, it was found that the natural product tanshinone IIA (TIIA) enhanced NK cell-mediated killing of non-small cell lung cancer (NSCLC) cells. TIIA in combination with adoptive transfer of NK cells synergistically suppressed the tumor growth of NSCLC cells in an immune-incompetent mouse model. Furthermore, TIIA significantly inhibited the tumor growth of Lewis lung cancer (LLC) in an immune-competent syngeneic mouse model, and such inhibitory effect was reversed by the depletion of NK cells. Moreover, TIIA increased expressions of ULBP1 and DR5 in NSCLC cells, and inhibition of DR5 and ULBP1 reduced the enhancement of NK cell-mediated lysis by TIIA. Besides, TIIA increased the levels of p-PERK, ATF4 and CHOP. Knockdown of ATF4 completely reversed the up-regulation of ULBP1 and DR5 by TIIA in all detected NSCLC cells, while knockdown of CHOP only partly reduced these enhanced expressions in small parts of NSCLC cells. These results demonstrated that TIIA could increase the susceptibility of NSCLC cells to NK cell-mediated lysis by up-regulating ULBP1 and DR5, suggesting that TIIA had a promising potential in cancer immunotherapy, especially in NK cell-based cancer immunotherapy.
自然杀伤 (NK) 细胞在癌症免疫疗法中有很大的潜力。然而，由于癌细胞的免疫逃逸，其治疗效果在临床上受到限制。因此，迫切需要开发新的方法来提高 NK 细胞的抗肿瘤免疫力。在本研究中，发现天然产物丹参酮 IIA (TIIA) 增强了 NK 细胞介导的非小细胞肺癌 (NSCLC) 细胞的杀伤作用。TIIA 与 NK 细胞过继转移联合协同抑制免疫无能小鼠模型中 NSCLC 细胞的肿瘤生长。此外，TIIA 显著抑制免疫相容同基因小鼠模型中的 Lewis 肺癌 (LLC) 肿瘤生长，而 NK 细胞耗竭则逆转了这种抑制作用。此外，TIIA 增加了 NSCLC 细胞中 ULBP1 和 DR5 的表达，而 DR5 和 ULBP1 的抑制减少了 TIIA 增强 NK 细胞介导的裂解作用。此外，TIIA 增加了 p-PERK、ATF4 和 CHOP 的水平。ATF4 的敲低完全逆转了 TIIA 在所有检测到的 NSCLC 细胞中对 ULBP1 和 DR5 的上调，而 CHOP 的敲低仅部分减少了部分 NSCLC 细胞中这些增强表达。这些结果表明，TIIA 通过上调 ULBP1 和 DR5 增加了 NSCLC 细胞对 NK 细胞介导的裂解的敏感性，提示 TIIA 在癌症免疫疗法中具有广阔的应用前景，特别是在基于 NK 细胞的癌症免疫疗法中。
