CD1d highly expressed on DCs reduces lung tumor burden by enhancing antitumor immunity
CD1d highly expressed on DCs reduces lung tumor burden by enhancing antitumor immunity
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CD1d 在 DC 上高表达，通过增强抗肿瘤免疫来减轻肺肿瘤负担
DOI：
10.3892/or.2019.7037
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发表时间：
2019-05-01
期刊：
影响因子：
4.2
通讯作者：
Liu, Ronghua
中科院分区：
文献类型：
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作者：
Li, Yifan;Zhao, Chujun;Liu, Ronghua
树突状细胞(DC)作为专职的抗原提呈细胞，在初始激活适应性抗肿瘤免疫中起着至关重要的作用。CD1d被认为是向NKT细胞递送磷脂和糖鞘糖脂抗原。然而，目前尚不清楚树突状细胞表面表达CD1d是否能够增强抗肿瘤免疫，尤其是T细胞相关免疫。我们观察到，在3LL荷瘤小鼠的DC上，CD1d主要表达，而CD1d的缺失促进了肿瘤的生长。值得注意的是，DC上CD1d的表达不仅是向NKT细胞递呈抗原所必需的，而且还显著促进了CD4+T细胞和CD8+T细胞的激活，尤其是细胞毒性T细胞。过继转移CD1d阳性树突状细胞(CD1d+DC)后，所有T细胞(NKT、CD4+T和CD8+T细胞)均上调CD69、CD107a和干扰素-γ，肿瘤生长受到抑制。在机制上，我们发现CD1d+DC伴随着高水平的共刺激分子(CD40、CD80、CD86)和MHCI/II的表达，这些分子是DC向T细胞递呈抗原所必需的。CD1d+DC具有较强的激活相关ERK1/2和NF-κB信号，而JAK2-STAT3/6信号是维持高水平CD1d的必需信号。在肺癌患者中，所有T细胞的抗肿瘤活性均随着CD1d+DC的增加而增强。对TCGA数据的分析表明，CD1d水平高表明患者的预后更好。总的来说，CD1d不仅通过靶向NKT，而且通过激活CD4+T和CD8+T细胞，增强了基于DC的抗肿瘤免疫。CD1d+树突状细胞在肿瘤免疫治疗中可能优于大量树突状细胞。
Dendritic cells (DCs), as professional antigen-presenting cells are essential for the initial activation of adaptive antitumor immunity. CD1d is considered to present phospholipid and glycosphingolipid antigens to NKT cells. However, it is currently unknown whether CD1d expression on DCs is capable of enhancing antitumor immunity, particularly T-cell related immunity. We observed that CD1d was predominantly expressed on DCs in 3LL tumor-bearing mice, whilst a deficiency of CD1d promoted tumor growth. Notably, CD1d expression on DCs was not only required for presenting antigen to NKT cells, but also markedly promoted CD4+T and CD8+T cell activation, particularly cytotoxic T cells. All the T cells (NKT, CD4+T and CD8+T cells) upregulated CD69, CD107a and IFN-γ after the adoptive transfer of CD1d-positive DCs (CD1d+DCs) and tumor growth was suppressed. With regard to the mechanism, we revealed that CD1d+DCs were concomitant with a higher expression of costimulatory molecules (CD40, CD80 and CD86) and MHCI/II, which are essential for DCs to present antigens to T cells. Consistently, CD1d+DCs displayed stronger activation-associated-ERK1/2 and NF-κB signals; whereas JAK2-STAT3/6 signaling was required for maintaining a high level of CD1d on DCs. In lung cancer patients, the antitumor activities of all the T cells were enhanced with the increase of CD1d+DCs. Analysis of TCGA data revealed that high levels of CD1d indicated better outcomes for patients. Collectively, CD1d enhanced DC-based antitumor immunity, not only by targeting NKT, but also by activating CD4+T and CD8+T cells. CD1d+DCs may be superior to the bulk population of DCs in cancer immunotherapy.