TLR7 Ligand Augments GM-CSF-Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells
TLR7 Ligand Augments GM-CSF-Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells
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DOI：
10.1158/2326-6066.cir-13-0143
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发表时间：
2014-06-01
影响因子：
10.1
通讯作者：
Tani, Kenzaburo
中科院分区：
文献类型：
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作者：
Narusawa, Megumi;Inoue, Hiroyuki;Tani, Kenzaburo
用经辐照的粒细胞巨噬细胞集落刺激因子（GM-CSF）转导的自体肿瘤细胞（GVAX）接种疫苗已显示可诱导治疗性抗肿瘤免疫。然而，其有效性是有限的。因此，我们试图通过识别肿瘤引流淋巴结（TDLN）中GM-CSF致敏的树突状细胞（GM-DC）中鲜为人知的关键通路来提高抗肿瘤效果。我们初步证实，同基因小鼠皮下注射低免疫原性刘易斯肺癌（LLC）细胞转导仙台病毒编码GM-CSF（LLC/SeV/GM）显着拒绝肿瘤生长。使用cDNA微阵列，我们发现，I型干扰素（IFN）相关基因的表达水平，主要表达在浆细胞样DC（pDC），显着上调TDLN衍生的GM-DC和集中在pDC。实际上，小鼠实验证明，当使用pDC耗尽或IFN α受体敲除（IFNAR（-/-））小鼠时，在用LLC/SeV/GM细胞处理的免疫活性小鼠中观察到的GM-CSF诱导的抗肿瘤免疫的有效诱导显著减弱。重要的是，在LLC和CT 26结肠癌荷瘤小鼠中，咪喹莫特与自体GVAX疗法的组合使用克服了GVAX单一疗法的难治性伴随耐受性。从机制上讲，用联合疫苗接种处理的小鼠在pDC中显示出与抗肿瘤表型相关的CD 86、CD 9和Siglec-H的表达水平增加，但在TDLN中降低了CD 4（+）CD 25（+）FoxP 3（+）调节性T细胞的比例。总的来说，这些发现表明，额外使用咪喹莫特来激活具有I型IFN产生的pDC，作为T细胞引发的正调节剂，可以增强GVAX疗法的免疫学抗肿瘤作用，从而为基于GM-CSF的癌症免疫疗法的理解和治疗提供有希望的光。(C)2014年AACR。
Vaccination with irradiated granulocyte macrophage colony-stimulating factor (GM-CSF)-transduced autologous tumor cells (GVAX) has been shown to induce therapeutic antitumor immunity. However, its effectiveness is limited. We therefore attempted to improve the antitumor effect by identifying little-known key pathways in GM-CSF-sensitized dendritic cells (GM-DC) in tumor-draining lymph nodes (TDLN). We initially confirmed that syngeneic mice subcutaneously injected with poorly immunogenic Lewis lung carcinoma (LLC) cells transduced with Sendai virus encoding GM-CSF (LLC/SeV/GM) remarkably rejected the tumor growth. Using cDNA microarrays, we found that expression levels of type I interferon (IFN)-related genes, predominantly expressed in plasmacytoid DCs (pDC), were significantly upregulated in TDLN-derived GM-DCs and focused on pDCs. Indeed, mouse experiments demonstrated that the effective induction of GM-CSF-induced antitumor immunity observed in immunocompetent mice treated with LLC/SeV/GM cells was significantly attenuated when pDC-depleted or IFN alpha receptor knockout (IFNAR(-/-)) mice were used. Importantly, in both LLC and CT26 colon cancer-bearing mice, the combinational use of imiquimod with autologous GVAX therapy overcame the refractoriness to GVAX monotherapy accompanied by tolerability. Mechanistically, mice treated with the combined vaccination displayed increased expression levels of CD86, CD9, and Siglec-H, which correlate with an antitumor phenotype, in pDCs, but decreased the ratio of CD4(+)CD25(+)FoxP3(+) regulatory T cells in TDLNs. Collectively, these findings indicate that the additional use of imiquimod to activate pDCs with type I IFN production, as a positive regulator of T-cell priming, could enhance the immunologic antitumor effects of GVAX therapy, shedding promising light on the understanding and treatment of GM-CSF-based cancer immunotherapy. (C) 2014 AACR.