Gastric cancer (GC) is the third most common cause of cancer‐related death worldwide. Invariant natural killer T (iNKT) cells are innate‐like cytotoxic T lymphocytes involved in tumor immune surveillance. They can be activated either through CD1d‐presented glycolipid antigens recognized by their invariant T‐cell receptor, cytokines or by sensing tumor‐associated stress‐induced ligands through the natural killer group 2, member D (NKG2D) receptor. Although the number and functionality of iNKT cells may be decreased in several types of cancer, here we show that GC patients presented a mild increase in iNKT cell frequencies and numbers in the blood compared with healthy donors. In GC patients, iNKT cells, expanded in vitro with α‐galactosyl ceramide and stimulated with phorbol 12‐myristate 13‐acetate and ionomycin, produced higher levels of interleukin‐2 and transforming growth factor‐beta, while their capacity to degranulate remained preserved. Because tumor‐derived epithelial cell adhesion molecule‐positive epithelial cells did not display surface CD1d, and NKG2D ligands (NKG2DLs) were detected in the gastric tumor milieu, we envisioned a role for NKG2D in iNKT cell functions. Peripheral iNKT cells from GC patients and controls presented similar levels of NKG2D; nevertheless, the percentages of interferon‐γ‐producing and CD107a‐positive iNKT cells from patients were reduced upon challenge with CD1d‐negative, NKG2DL‐positive K562 cells, suggesting a compromised response by iNKT cells in GC patients, which may not result from impaired NKG2D/NKG2DL signaling. The decreased response of iNKT cells may explain the fact that higher frequencies of circulating iNKT cells did not confer a survival benefit for GC patients. Therefore, functional impairment of iNKT cells in GC may contribute to tumor immune escape and favor disease progression.

中文翻译：

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胃癌患者不变的自然杀伤T细胞介导的抗肿瘤免疫反应降低

胃癌（GC）是全球第三大与癌症相关的死亡原因。不变的自然杀伤T细胞（iNKT）是与肿瘤免疫监视有关的先天性细胞毒性T淋巴细胞。它们可以通过被其恒定T细胞受体，细胞因子识别的CD1d呈递糖脂抗原激活，也可以通过天然杀伤剂第2组D成员（NKG2D）感知与肿瘤相关的应激诱导的配体而被激活。尽管在几种类型的癌症中iNKT细胞的数量和功能可能会降低，但在这里我们显示，与健康供体相比，GC患者的iNKT细胞频率和血液中的数量有轻度增加。在GC患者中，iNKT细胞在体外扩增用α-半乳糖基神经酰胺和佛波醇12-肉豆蔻酸酯13-乙酸酯和离子霉素刺激，可以产生更高水平的白介素-2和转化生长因子-β，而它们的脱粒能力得以保留。由于肿瘤来源的上皮细胞粘附分子阳性的上皮细胞不显示表面CD1d，并且在胃肿瘤环境中检测到NKG2D配体（NKG2DLs），因此我们设想了NKG2D在iNKT细胞功能中的作用。来自GC患者和对照组的外周iNKT细胞表现出相似的NKG2D水平。然而，用CD1d阴性，NKG2DL阳性的K562细胞攻击后，患者产生的干扰素γ和CD107a阳性的iNKT细胞的百分比降低了，这表明iNKT细胞在GC患者中的反应受到损害，这可能不是受损的结果NKG2D / NKG2DL信令。iNKT细胞应答的降低可能解释了这样一个事实，即循环中的iNKT细胞的较高频率并未给GC患者带来生存益处。因此，iNKT细胞在GC中的功能受损可能有助于肿瘤免疫逃逸并促进疾病进展。