In situ regulation of DC subsets and T cells mediates tumor regression in mice.
In situ regulation of DC subsets and T cells mediates tumor regression in mice.
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DOI：
10.1126/scitranslmed.3000359
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发表时间：
2009-11-25
影响因子：
17.1
通讯作者：
Mooney DJ
中科院分区：
文献类型：
--
作者：
Ali OA;Emerich D;Dranoff G;Mooney DJ
疫苗对已确诊癌症的患者基本上无效，因为晚期疾病需要有效且持续激活 CD8+ 细胞毒性 T 淋巴细胞 (CTL) 来杀死肿瘤细胞并清除疾病。最近的研究阐明，树突状细胞 (DC) 的亚群专门从事抗原交叉呈递和细胞因子的产生，这些细胞因子调节 CTL 和 T 调节 (Treg) 细胞，从而关闭效应 T 细胞反应。在本研究中，我们提出了这样的假设：DC 网络，特别是浆细胞样 DC（pDC）和 CD8（+）DC 的协调调节可以显着增强小鼠的宿主免疫力。我们使用功能化生物材料，结合炎症细胞因子、免疫危险信号和肿瘤裂解物的各种组合来控制宿主 DC 群体的原位激活和定位。 pDC和CD8(+) DC的数量以及白细胞介素-12 (IL-12)的内源性产生均与保护性抗肿瘤免疫的强度和有效CD8(+) CTL的产生密切相关。通过这种方法进行的疫苗接种可以长时间维持局部和全身 CTL 反应，同时在抗原清除过程中抑制 FoxP3 Treg 活性，从而使远处和已形成的黑色素瘤完全消退。这种疫苗作为针对侵袭性和大肿瘤的单一疗法的功效可能是由于疫苗部位持续危险和抗原信号传导诱导的 pDC 和 CD8(+) DC 局部活性的结果。这些结果表明 DC 亚群的关键模式与治疗、抗肿瘤反应的演变相关，并为未来的疫苗设计提供了模板。
Vaccines are largely ineffective for patients with established cancer, as advanced disease requires potent and sustained activation of CD8(+) cytotoxic T lymphocytes (CTL) to kill tumor cells and clear the disease. Recent studies have elucidated that subsets of dendritic cells (DCs) specialize in antigen cross-presentation and in the production of cytokines, which regulate both CTLs and T regulatory (Treg) cells that shut down effector T cell responses. In this study we have addressed the hypothesis that coordinated regulation of a DC network, and plasmacytoid DCs (pDCs) and CD8(+) DCs in particular, could dramatically enhance host immunity in mice. We used functionalized biomaterials incorporating various combinations of an inflammatory cytokine, immune danger signal and tumor lysates to control the activation and localization of host DC populations in situ. The numbers of pDCs and CD8(+) DCs, and the endogenous production of interleukin-12 (IL-12), all correlated strongly with the magnitude of protective anti-tumor immunity and the generation of potent CD8(+) CTLs. Vaccination by this method maintained local and systemic CTL responses for extended periods, while inhibiting FoxP3 Treg activity during antigen clearance, resulting in complete regression of distant and established melanoma tumors. The efficacy of this vaccine as a monotherapy against invasive and large tumors may be a result of the local activity of pDCs and CD8(+) DCs induced by persistent danger and antigen signaling at the vaccine site. These results indicate that a critical pattern of DC subsets correlates with the evolution of therapeutic, anti-tumor responses and provide a template for future vaccine design.