Laboratory of Cellular Immunobiology, Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, New York, USA.
Clin Cancer Res. 2011 Apr 1;17(7):1984-97. doi: 10.1158/1078-0432.CCR-10-3421. Epub 2011 Feb 25.
We compared the efficacy of human Langerhans cells (LC) as tumor immunogens in vivo with monocyte-derived dendritic cells (moDC) and investigated how interleukin 15 (IL15) supports optimal DC-stimulated antitumor immunity.
American Joint Committee on Cancer stage III/IV melanoma patients participated in this first clinical trial comparing melanoma peptide-pulsed LC with moDC vaccines (NCT00700167, www.ClinicalTrials.gov). Correlative studies evaluated mechanisms mediating IL15 support of DC-stimulated antitumor immunity.
Both DC vaccines were safe and immunogenic for melanoma antigens. LC-based vaccines stimulated significantly greater tyrosinase-HLA-A*0201 tetramer reactivity than the moDC-based vaccines. The two DC subtypes were otherwise statistically comparable, in contrast to extensive prior data in vitro showing LC superiority. LCs synthesize much more IL15 than moDCs and stimulate significantly more antigen-specific lymphocytes with a cytolytic IFN-γ profile even without exogenous IL15. When supplemented by low-dose IL15, instead of IL2, moDCs stimulate 5 to 6 logs more tumor antigen-specific effector memory T cells (T(EMRA)) over 3 to 4 weeks in vitro. IL2 and IL15 can be synergistic in moDC stimulation of cytolytic T cells. IL15 promotes T-cell expression of the antiapoptotic bcl-2 and inhibits candidate regulatory T-cell (Treg) expansion after DC stimulation, countering two effects of IL2 that do not foster tumor immunity.
MoDC-based vaccines will require exogenous IL15 to achieve clinical efficacy. Alternatively, LCs can couple the endogenous production of IL15 with potent T-cell stimulatory activity. Optimization of full-length tumor antigen expression for processing into multiple immunogenic peptides for presentation by both class I and II MHC therefore merits emphasis to support more effective antitumor immunity stimulated by LCs.
我们比较了人朗格汉斯细胞（LC）作为肿瘤免疫原在体内的功效与单核细胞衍生的树突状细胞（moDC），并研究了白细胞介素 15（IL15）如何支持最佳的 DC 刺激抗肿瘤免疫。
美国癌症联合委员会（AJCC）分期 III/IV 期黑色素瘤患者参加了这项比较黑色素瘤肽脉冲 LC 与 moDC 疫苗的首次临床试验（NCT00700167，www.ClinicalTrials.gov）。相关研究评估了介导 IL15 支持 DC 刺激抗肿瘤免疫的机制。
两种 DC 疫苗对黑色素瘤抗原均安全且具有免疫原性。基于 LC 的疫苗刺激的酪氨酸酶-HLA-A*0201 四聚体反应明显高于基于 moDC 的疫苗。这两种 DC 亚型在其他方面具有统计学可比性，与体外大量先前数据显示 LC 的优势形成对比。LC 比 moDC 合成更多的 IL15，并在没有外源性 IL15 的情况下刺激明显更多的抗原特异性淋巴细胞，具有细胞毒性 IFN-γ 特征。当用低剂量的 IL15 替代 IL2 补充时，moDC 在体外 3 至 4 周内刺激多达 5 至 6 个对数的肿瘤抗原特异性效应记忆 T 细胞（T(EMRA)）。IL2 和 IL15 在 moDC 刺激细胞毒性 T 细胞方面可以协同作用。IL15 促进 T 细胞表达抗凋亡 bcl-2，并抑制 DC 刺激后候选调节性 T 细胞（Treg）的扩增，这抵消了 IL2 不促进肿瘤免疫的两个作用。
基于 moDC 的疫苗将需要外源性 IL15 才能达到临床疗效。或者，LC 可以将内源性 IL15 的产生与强大的 T 细胞刺激活性结合起来。因此，优化全长肿瘤抗原的表达以加工成多种免疫原性肽，用于 I 类和 II 类 MHC 的呈递，值得强调，以支持由 LC 刺激更有效的抗肿瘤免疫。
