人类双阴性 T 细胞通过配体依赖的机制靶向肺癌，这些机制可以通过 IL-15 增强。
Human double negative T cells target lung cancer via ligand-dependent mechanisms that can be enhanced by IL-15.
机构信息
Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
出版信息
J Immunother Cancer. 2019 Jan 22;7(1):17. doi: 10.1186/s40425-019-0507-2.
BACKGROUND
The advents of novel immunotherapies have revolutionized the treatment of cancer. Adoptive cellular therapies using chimeric antigen receptor T (CAR-T) cells have achieved remarkable clinical responses in B cell leukemia and lymphoma but the effect on solid tumors including lung cancer is limited. Here we present data on the therapeutic potential of allogeneic CD3CD4CD8 double negative T (DNT) cells as a new cellular therapy for the treatment of lung cancer and underlying mechanisms.
METHODS
DNTs were enriched and expanded ex vivo from healthy donors and phenotyped by flow cytometry. Functionally, their cytotoxicity was determined against primary and established non-small-cell lung cancer (NSCLC) cell lines in vitro or through in vivo adoptive transfer into xenograft models. Mechanistic analysis was performed using blocking antibodies against various cell surface and soluble markers. Furthermore, the role of IL-15 on DNT function was determined.
RESULTS
We demonstrated that ex vivo expanded DNTs can effectively lyse various human NSCLC cells in vitro and inhibit tumor growth in xenograft models. Expanded DNTs have a cytotoxic phenotype, as they express NKp30, NKG2D, DNAM-1, membrane TRAIL (mTRAIL), perforin and granzyme B, and secrete IFNγ and soluble TRAIL (sTRAIL). DNT-mediated cytotoxicity was dependent on a combination of tumor-expressed ligands for NKG2D, DNAM-1, NKp30 and/or receptors for TRAIL, which differ among different NSCLC cell lines. Furthermore, stimulation of DNTs with IL-15 increased expression of effector molecules on DNTs, their TRAIL production and cytotoxicity against NSCLC in vitro and in vivo.
CONCLUSION
Healthy donor-derived DNTs can target NSCLC in vitro and in vivo. DNTs recognize tumors via innate receptors which can be up-regulated by IL-15. DNTs have the potential to be used as a novel adoptive cell therapy for lung cancer either alone or in combination with IL-15.
背景
新型免疫疗法的出现彻底改变了癌症的治疗方式。嵌合抗原受体 T（CAR-T）细胞的过继细胞疗法在 B 细胞白血病和淋巴瘤中取得了显著的临床疗效，但对包括肺癌在内的实体瘤的疗效有限。在这里，我们展示了同种异体 CD3CD4CD8 双阴性 T（DNT）细胞作为一种新的细胞疗法治疗肺癌及其潜在机制的治疗潜力的数据。
方法
从健康供体中体外富集和扩增 DNT 细胞，并通过流式细胞术进行表型分析。功能上，通过体外或通过过继转移到异种移植模型中，检测它们对原发性和已建立的非小细胞肺癌（NSCLC）细胞系的细胞毒性。使用针对各种细胞表面和可溶性标志物的阻断抗体进行机制分析。此外，还确定了 IL-15 对 DNT 功能的作用。
结果
我们证明了体外扩增的 DNT 细胞可以有效地裂解各种人 NSCLC 细胞，并抑制异种移植模型中的肿瘤生长。扩增的 DNT 细胞具有细胞毒性表型，因为它们表达 NKp30、NKG2D、DNAM-1、膜 TRAIL（mTRAIL）、穿孔素和颗粒酶 B，并分泌 IFNγ 和可溶性 TRAIL（sTRAIL）。DNT 介导的细胞毒性依赖于肿瘤表达的 NKG2D、DNAM-1、NKp30 和/或 TRAIL 受体的配体的组合，这些配体在不同的 NSCLC 细胞系中有所不同。此外，用 IL-15 刺激 DNT 细胞可增加 DNT 细胞上效应分子的表达、它们对 NSCLC 的 TRAIL 产生和细胞毒性，无论是在体外还是体内。
结论
健康供体来源的 DNT 可以在体外和体内靶向 NSCLC。DNT 通过先天受体识别肿瘤，这些受体可以被 IL-15 上调。DNT 具有作为一种新的过继细胞疗法用于肺癌的潜力，无论是单独使用还是与 IL-15 联合使用。
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