Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China.
Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
J Exp Clin Cancer Res. 2019 Mar 11;38(1):123. doi: 10.1186/s13046-019-1126-y.
Though immune checkpoint blockade (ICB) against PD-1 has shown success in the treatment of lung cancer, not all patients respond. We have previously shown that adoptive transfer of double negative T (DNT) cells expanded from healthy donors can target leukemia but their role in treating established lung cancer is not clear. Here we explore the role of human DNT cells in targeting late-stage established lung cancer either alone or in combination with Nivolumab (anti-PD-1 antibody) and describe underlying mechanisms.
DNT cells from resected lung cancer tissue of patients were analyzed by flow cytometry to determine their infiltration and PD-1 expression. Expansion capacity and anti-tumor function of lung cancer patient and healthy donor DNT cells were compared. Late-stage lung cancer xenograft models were developed to determine the anti-tumor effect of DNT cells alone or in combination with anti-PD-1 antibody, and the level of tumor-infiltrating DNT cells was quantified by histology and characterized by flow cytometry.
Patient-derived tumor infiltrating lymphocytes contained a lower frequency of DNT cells with a higher expression of PD-1 relative to normal lung tissue. Ex vivo expanded patient- and healthy donor-derived DNT cells showed similar levels of cytotoxicity against lung cancer cells in vitro. Healthy donor-derived DNT cells significantly inhibited the growth of late-stage lung cancer xenografts, which was further augmented by anti-PD-1 through increased DNT cell tumor infiltration.
This study supports the use of DNT cells for adoptive cellular therapy against lung cancer either alone or in combination with anti-PD-1.
尽管针对 PD-1 的免疫检查点阻断 (ICB) 在治疗肺癌方面取得了成功，但并非所有患者都有反应。我们之前已经表明，从健康供体中扩增的双阴性 T (DNT) 细胞的过继转移可以靶向白血病，但它们在治疗已建立的肺癌中的作用尚不清楚。在这里，我们探索了 DNT 细胞单独或与 Nivolumab（抗 PD-1 抗体）联合靶向晚期已建立的肺癌的作用，并描述了潜在的机制。
通过流式细胞术分析来自患者切除的肺癌组织的 DNT 细胞，以确定其浸润和 PD-1 表达。比较了肺癌患者和健康供体 DNT 细胞的扩增能力和抗肿瘤功能。建立晚期肺癌异种移植模型，以确定 DNT 细胞单独或与抗 PD-1 抗体联合的抗肿瘤作用，并通过组织学和流式细胞术定量肿瘤浸润 DNT 细胞的水平。
与正常肺组织相比，患者来源的肿瘤浸润淋巴细胞中 DNT 细胞的频率较低，PD-1 表达较高。体外扩增的患者和健康供体来源的 DNT 细胞对肺癌细胞的体外细胞毒性相似。健康供体来源的 DNT 细胞显著抑制晚期肺癌异种移植的生长，通过增加 DNT 细胞肿瘤浸润，与抗 PD-1 联合使用可进一步增强。
这项研究支持使用 DNT 细胞进行过继细胞疗法治疗肺癌，无论是单独使用还是与抗 PD-1 联合使用。
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