Kuhn Sabine, Yang Jianping, Ronchese Franca
Malaghan Institute of Medical Research , Wellington , New Zealand.
Front Immunol. 2015 Nov 23;6:584. doi: 10.3389/fimmu.2015.00584. eCollection 2015.
Tumors harbor several populations of dendritic cells (DCs) with the ability to prime tumor-specific T cells. However, these T cells mostly fail to differentiate into armed effectors and are unable to control tumor growth. We have previously shown that treatment with immunostimulatory agents at the tumor site can activate antitumor immune responses and is associated with the appearance of a population of monocyte-derived DCs (moDCs) in the tumor and tumor-draining lymph node (dLN). Here, we use depletion of DCs or monocytes and monocyte transfer to show that these moDCs are critical to the activation of antitumor immune responses. Treatment with the immunostimulatory agents monosodium urate crystals and Mycobacterium smegmatis induced the accumulation of monocytes in the dLN, their upregulation of CD11c and MHCII, and expression of iNOS, TNFα, and IL12p40. Blocking monocyte entry into the lymph node and tumor through neutralization of the chemokine CCL2 or inhibition of colony-stimulating factor-1 receptor signaling prevented the generation of moDCs, the infiltration of tumor-specific T cells into the tumor, and antitumor responses. In a reciprocal fashion, monocytes transferred into mice depleted of CD11c(+) cells were sufficient to rescue CD8(+) T cell priming in lymph node and delay tumor growth. Thus, monocytes exposed to the appropriate conditions become powerful activators of tumor-specific CD8(+) T cells and antitumor immunity.
肿瘤中存在几类具有启动肿瘤特异性T细胞能力的树突状细胞（DC）。然而，这些T细胞大多无法分化为有活性的效应细胞，也无法控制肿瘤生长。我们之前已经表明，在肿瘤部位用免疫刺激剂进行治疗可以激活抗肿瘤免疫反应，并且与肿瘤及肿瘤引流淋巴结（dLN）中一群单核细胞来源的DC（moDC）的出现有关。在此，我们通过DC或单核细胞的清除以及单核细胞转移实验表明，这些moDC对于激活抗肿瘤免疫反应至关重要。用免疫刺激剂尿酸钠晶体和耻垢分枝杆菌进行治疗可诱导单核细胞在dLN中积聚，使其CD11c和MHCII上调，并表达诱导型一氧化氮合酶（iNOS）、肿瘤坏死因子α（TNFα）和白细胞介素12p40（IL12p40）。通过中和趋化因子CCL2或抑制集落刺激因子-1受体信号传导来阻断单核细胞进入淋巴结和肿瘤，可阻止moDC的产生、肿瘤特异性T细胞向肿瘤的浸润以及抗肿瘤反应。反之，将单核细胞转移到CD11c(+)细胞耗竭的小鼠体内足以挽救淋巴结中CD8(+) T细胞的启动并延缓肿瘤生长。因此，暴露于适当条件下的单核细胞会成为肿瘤特异性CD8(+) T细胞和抗肿瘤免疫的强大激活剂。
