CD137L树突状细胞诱导针对癌症相关病毒的有效应答，并将人

StephenW

Cancer Immunol Immunother. 2018 Mar 5. doi: 10.1007/s00262-018-2144-x. [Epub ahead of print]
CD137L dendritic cells induce potent response against cancer-associated viruses and polarize human CD8+ T cells to Tc1 phenotype.
Dharmadhikari B1, Nickles E1, Harfuddin Z1,2, Ishak NDB1, Zeng Q1, Bertoletti A3, Schwarz H4,5.
Author information

1
    Department of Physiology and Immunology Programme, National University of Singapore (NUS), 2 Medical Dr., Singapore, 117593, Singapore.
2
    NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore, 117456, Singapore.
3
    Duke-NUS Graduate Medical School, Singapore, 169857, Singapore.
4
    Department of Physiology and Immunology Programme, National University of Singapore (NUS), 2 Medical Dr., Singapore, 117593, Singapore. [email protected].
5
    NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore, 117456, Singapore. [email protected].

Abstract

Therapeutic tumor vaccination based on dendritic cells (DC) is safe; however, its efficacy is low. Among the reasons for only a subset of patients benefitting from DC-based immunotherapy is an insufficient potency of in vitro generated classical DCs (cDCs), made by treating monocytes with GM-CSF + IL-4 + maturation factors. Recent studies demonstrated that CD137L (4-1BBL, TNFSF9) signaling differentiates human monocytes to a highly potent novel type of DC (CD137L-DCs) which have an inflammatory phenotype and are closely related to in vivo DCs. Here, we show that CD137L-DCs induce potent CD8+ T-cell responses against Epstein-Barr virus (EBV) and Hepatitis B virus (HBV), and that T cells primed by CD137L-DCs more effectively lyse EBV+ and HBV+ target cells. The chemokine profile of CD137L-DCs identifies them as inflammatory DCs, and they polarize CD8+ T cells to a Tc1 phenotype. Expression of exhaustion markers is reduced on T cells activated by CD137L-DCs. Furthermore, these T cells are metabolically more active and have a higher capacity to utilize glucose. CD137L-induced monocyte to DC differentiation leads to the formation of AIM2 inflammasome, with IL-1beta contributing to CD137L-DCs possessing a stronger T cell activation ability. CD137L-DCs are effective in crosspresentation. PGE2 as a maturation factor is required for enhancing migration of CD137L-DCs but does not significantly reduce their potency. This study shows that CD137L-DCs have a superior ability to activate T cells and to induce potent Tc1 responses against the cancer-causing viruses EBV and HBV which suggest CD137L-DCs as promising candidates for DC-based tumor immunotherapy.
KEYWORDS:

CD137; CD137L-DC; Dendritic cells; Epstein–Barr virus; Hepatitis B virus; Inflammasome

PMID:
    29508025
DOI:
    10.1007/s00262-018-2144-x

StephenW

癌症免疫学Immunother。 2018年3月5日doi：10.1007 / s00262-018-2144-x。 [电子版提前打印]
CD137L树突状细胞诱导针对癌症相关病毒的有效应答，并将人类CD8 + T细胞极化至Tc1表型。
Dharmadhikari B1，Nickles E1，Harfuddin Z1,2，Ishak NDB1，Zeng Q1，Bertoletti A3，Schwarz H4,5。
作者信息

1
    新加坡国立大学生理学与免疫学系（新加坡国立大学医学院），2医学博士，新加坡，117593，新加坡。
2
    新加坡国立大学综合科学与工程研究生院新加坡117456，新加坡。
3
    杜克大学国立大学研究生医学院，新加坡，169857，新加坡。
4
    新加坡国立大学生理学与免疫学系（新加坡国立大学医学院），2医学博士，新加坡，117593，新加坡。 [email protected]。
五
    新加坡国立大学综合科学与工程研究生院新加坡117456，新加坡。 [email protected]。

抽象

基于树突状细胞（DC）的治疗性肿瘤疫苗接种是安全的;然而，其疗效低。只有一小部分受益于基于DC的免疫疗法的患者的原因是通过用GM-CSF + IL-4 +成熟因子处理单核细胞而产生的体外产生的经典DC（cDC）的效力不足。最近的研究表明CD137L（4-1BBL，TNFSF9）信号将人单核细胞分化成具有炎症表型并与体内DC密切相关的高效新型DC（CD137L-DC）。在这里，我们显示CD137L-DC诱导针对EB病毒（EBV）和乙型肝炎病毒（HBV）的有效CD8 + T细胞应答，并且由CD137L-DC引发的T细胞更有效地裂解EBV +和HBV +靶细胞。 CD137L-DC的趋化因子特征将它们鉴定为炎性DC，并且它们使CD8 + T细胞极化成Tc1表型。在由CD137L-DC激活的T细胞中，耗尽标志物的表达减少。此外，这些T细胞代谢更活跃，并具有更高的利用葡萄糖的能力。 CD137L诱导的单核细胞向DC分化导致形成AIM2炎性体，其中IL-1beta促成具有更强的T细胞活化能力的CD137L-DC。 CD137L-DC在交叉表达中是有效的。作为成熟因子的PGE2对于增强CD137L-DC的迁移是必需的，但不会显着降低它们的效力。该研究表明CD137L-DC具有优良的激活T细胞的能力并诱导针对致癌病毒EBV和HBV的强效Tc1应答，这表明CD137L-DC作为用于基于DC的肿瘤免疫疗法的有希望的候选者。
关键词：

CD137; CD137L-DC;树突状细胞;爱泼斯坦 - 巴尔病毒;乙型肝炎病毒;炎性

结论：
    29508025
DOI：
    10.1007 / s00262-018-2144-X