Malaghan Institute of Medical Research, Wellington, New Zealand.
Haematologica. 2013 Mar;98(3):376-84. doi: 10.3324/haematol.2012.072835. Epub 2012 Oct 12.
Invariant natural killer T cells recognize glycolipid antigens such as α-galactosylceramide presented by CD1d. In preclinical models of B-cell malignancies, α-galactosylceramide is an adjuvant to tumor vaccination, enhancing tumor-specific T-cell responses and prolonging survival. However, numerical and functional invariant natural killer T-cell defects exist in patients with some cancers. Our aim was to assess this axis in patients with chronic lymphocytic leukemia. The numbers of circulating invariant natural killer T cells and the expression of CD1d on antigen-presenting cells were evaluated in patients with chronic lymphocytic leukemia and age-matched controls. Cytokine profile and in vitro proliferative capacity were determined. Patient- and control-derived invariant natural killer T-cell lines were generated and characterized, and allogeneic and autologous responses to α-galactosylce-ramide-treated leukemia cells were assessed. Absolute numbers and phenotype of invariant natural killer T cells were normal in patients with untreated chronic lymphocytic leukemia, and cytokine profile and proliferative capacity were intact. Chemotherapy-treated patients had reduced numbers of invariant natural killer T cells and myeloid dendritic cells, but α-galactosylceramide-induced proliferation was preserved. Invariant natural killer T-cell lines from patients lysed CD1d-expressing targets. Irradiated α-galactosylceramide-treated leukemic cells elicited allogeneic and autologous invariant natural killer T-cell proliferation, and α-galactosylceramide treatment led to increased proliferation of conventional T cells in response to tumor. In conclusion, the invariant natural killer T-cell and CD1d axis is fundamentally intact in patients with early-stage chronic lymphocytic leukemia and, despite reduced circulating numbers, function is retained in fludarabine-treated patients. Immunotherapies exploiting the adjuvant effect of α-galactosylceramide may be feasible.
天然不变型自然杀伤 T 细胞识别糖脂抗原，如 CD1d 呈递的 α-半乳糖基神经酰胺。在 B 细胞恶性肿瘤的临床前模型中，α-半乳糖基神经酰胺是肿瘤疫苗接种的佐剂，增强了肿瘤特异性 T 细胞反应并延长了生存时间。然而，一些癌症患者存在天然不变型自然杀伤 T 细胞数量和功能的缺陷。我们的目的是评估慢性淋巴细胞白血病患者的这一轴。评估慢性淋巴细胞白血病患者和年龄匹配的对照者的循环天然不变型自然杀伤 T 细胞数量和抗原呈递细胞上 CD1d 的表达。测定细胞因子谱和体外增殖能力。生成和表征患者和对照者来源的天然不变型自然杀伤 T 细胞系，并评估对 α-半乳糖基神经酰胺处理的白血病细胞的同种异体和自体反应。未经治疗的慢性淋巴细胞白血病患者的天然不变型自然杀伤 T 细胞的绝对数量和表型正常，细胞因子谱和增殖能力完整。化疗治疗的患者天然不变型自然杀伤 T 细胞和髓样树突状细胞数量减少，但α-半乳糖基神经酰胺诱导的增殖得以保留。来自患者的天然不变型自然杀伤 T 细胞系可裂解表达 CD1d 的靶标。照射的 α-半乳糖基神经酰胺处理的白血病细胞引发同种异体和自体天然不变型自然杀伤 T 细胞增殖，并且 α-半乳糖基神经酰胺处理导致肿瘤反应中常规 T 细胞的增殖增加。总之，早期慢性淋巴细胞白血病患者的天然不变型自然杀伤 T 细胞和 CD1d 轴基本完整，尽管循环数量减少，但在氟达拉滨治疗的患者中保留了功能。利用 α-半乳糖基神经酰胺佐剂作用的免疫疗法可能是可行的。
