Characterization of myeloid leukocytes and soluble mediators in pancreatic cancer: importance of myeloid-derived suppressor cells
Characterization of myeloid leukocytes and soluble mediators in pancreatic cancer: importance of myeloid-derived suppressor cells
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胰腺癌中骨髓白细胞和可溶性介质的特征：骨髓源性抑制细胞的重要性
DOI：
10.1080/2162402x.2014.998519
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发表时间：
2015-01-01
期刊：
影响因子：
7.2
通讯作者：
Bazhin, Alexandr V.
中科院分区：
文献类型：
--
作者：
Karakhanova, Svetlana;Link, Julia;Bazhin, Alexandr V.
胰腺导管腺癌(PDAC)是世界上最致命的癌症之一。PDAC细胞激活肿瘤特异性免疫反应，但同时也引发强烈的免疫抑制。我们发现，PDAC细胞产生大量的慢性炎症介质，而PDAC肿瘤建立了与肿瘤进展相关的免疫抑制细胞因子环境。我们观察到，在小鼠PDAC肿瘤中，树突状细胞(DC)的频率很低，巨噬细胞和髓系来源的抑制细胞(MDSC)显著聚集。在切除的PDAC患者的外周血中也显示出强烈的MDSC积聚。在免疫抑制的背景下，DC和巨噬细胞似乎在PDAC模型中不起重要作用，而MDSC是高度抑制的，它们的积聚与PDAC进展过程中肿瘤内VEGF浓度的增加有关。应用磷酸二酯酶-5抑制剂西地那非可延长携带PDAC的雌性小鼠的存活时间，这是由于MDSC频率和全身血管内皮生长因子水平降低所致。这导致了抗癌免疫反应的恢复，表现为T淋巴细胞功能的恢复，肿瘤中常规CD_4+T细胞的频率和携带PDAC的小鼠血清中干扰素γ水平的增加。因此，MDSC强烈地参与了PDAC相关的免疫抑制，它们的耗竭可能为PDAC的治疗创造新的途径。
Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. PDAC cells activate tumor-specific immune responses but simultaneously trigger a strong immunosuppression. We showed that PDAC cells produce high amount of chronic inflammatory mediators and PDAC tumors build an immunosuppressive cytokine milieu, which correlates with tumor progression. We observed a low frequency of dendritic cells (DC) and a pronounced accumulation of macrophages and myeloid-derived suppressor cells (MDSC) in murine PDAC tumors. A strong accumulation of MDSC has also been demonstrated in the peripheral blood of resected PDAC patients. While DC and macrophages seem not to play a significant role in this PDAC model in the context of immunosuppression, MDSC are highly suppressive, and their accumulation is associated with an increase in intratumoral VEGF concentration during the PDAC progression. Application of the phosphodiesterase-5 inhibitor sildenafil led to a prolonged survival of PDAC-bearing female mice, which was due to the decrease in MDSC frequencies and in the systemic VEGF level. This led to a restoration of anticancer immune responses, manifested in the recovery of T lymphocyte functions and in an increase in the frequency of conventional CD4+ T cells in tumors and IFNγ level in serum of PDAC-bearing mice. Thus, MDSC are strongly involved in the PDAC-associated immunosuppression and that their depletion could create new approaches for therapy of PDAC.