Harnessing Natural Killer Immunity in Metastatic SCLC
Harnessing Natural Killer Immunity in Metastatic SCLC
复制标题
DOI：
10.1016/j.jtho.2020.05.008
复制
发表时间：
2020-09-01
影响因子：
20.4
通讯作者：
Sutherland, Kate D.
中科院分区：
文献类型：
--
作者：
Best, Sarah A.;Hess, Jonas B.;Sutherland, Kate D.
前言：小细胞肺癌是最具侵袭性的肺癌亚型，虽然大多数患者最初对以铂为基础的化疗有反应，但耐药性迅速发展。免疫疗法在肺癌的治疗中是有希望的；然而，小细胞肺癌患者的总体反应很差，这突显了替代方法的必要性。自然杀伤(NK)细胞是一种不需要对肿瘤细胞表面抗原致敏的以T细胞为基础的免疫疗法的替代方法。方法：采用新鲜标本的流式细胞术和生物信息学分析相结合的方法研究人小细胞肺癌的免疫表型。将小鼠小细胞肺癌产生的细胞系移植到缺乏关键细胞毒性免疫细胞的小鼠体内。用组织学和流式细胞术检测肿瘤的生长、转移和CD8刺激素T细胞和NK细胞的激活情况。结果：人小细胞肺癌的转录本分析显示出异质性的免疫检查点和细胞毒特征图谱。利用复杂的基因工程小鼠模型，我们报告了NK细胞的缺失，而不是CD8刺状T细胞的缺失，大大增强了小细胞肺癌肿瘤细胞在体内的转移扩散。此外，通过增强IL-15或转化生长因子-β信号通路激活NK细胞活性可改善小细胞肺癌的转移，联合抗程序性细胞死亡-1治疗可增强这种作用。结论：这些经验性的发现为利用NK细胞的抗肿瘤功能治疗小细胞肺癌提供了理论依据。此外，SCLC亚型独特的免疫学特征揭示了一种未被认识的异质性水平，这值得在免疫治疗的患者分层中进行进一步的研究。
Introduction: SCLC is the most aggressive subtype of lung cancer, and though most patients initially respond to platinum-based chemotherapy, resistance develops rapidly. Immunotherapy holds promise in the treatment of lung cancer; however, patients with SCLC exhibit poor overall responses highlighting the necessity for alternative approaches. Natural killer (NK) cells are an alternative to T cell-based immunotherapies that do not require sensitization to antigens presented on the surface of tumor cells.Methods: We investigated the immunophenotype of human SCLC tumors by both flow cytometry on fresh samples and bioinformatic analysis. Cell lines generated from murine SCLC were transplanted into mice lacking key cytotoxic immune cells. Subcutaneous tumor growth, metastatic dissemination, and activation of CD8 thorn T and NK cells were evaluated by histology and flow cytometry.Results: Transcriptomic analysis of human SCLC tumors revealed heterogeneous immune checkpoint and cytotoxic signature profiles. Using sophisticated, genetically engineered mouse models, we reported that the absence of NK cells, but not CD8 thorn T cells, substantially enhanced metastatic dissemination of SCLC tumor cells in vivo. Moreover, hyperactivation of NK cell activity through augmentation of interleukin-15 or transforming growth factor-beta signaling pathways ameliorated SCLC metastases, an effect that was enhanced when combined with antiprogrammed cell death-1 therapy.Conclusions: These proof-of-principle findings provide a rationale for exploiting the antitumor functions of NK cells in the treatment of patients with SCLC. Moreover, the distinct immune profiles of SCLC subtypes reveal an unappreciated level of heterogeneity that warrants further investigation in the stratification of patients for immunotherapy.