Down-regulation of PLCγ2-β-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer.
Down-regulation of PLCγ2-β-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer.
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DOI：
10.1084/jem.20130281
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发表时间：
2013-10-21
期刊：
影响因子：
--
通讯作者：
Faccio R
中科院分区：
文献类型：
--
作者：
Capietto AH;Kim S;Sanford DE;Linehan DC;Hikida M;Kumosaki T;Novack DV;Faccio R
肿瘤相关骨髓细胞中PLCγ2和β-连环蛋白信号传导的下调允许它们在小鼠和人类中扩增和肿瘤生长。骨髓来源的抑制细胞（MDSC）有利于肿瘤的促进，主要是通过抑制许多癌症中的抗肿瘤T细胞反应。虽然T细胞抑制的机制已经确立，但导致MDSC在荷瘤宿主的骨髓和次级淋巴器官中蓄积的途径仍不清楚。我们证明，MDSC中PLCγ2信号的下调是其在肿瘤进展期间异常扩增的原因。PLCγ2−/− MDSC对CD 8 + T细胞的免疫抑制活性强于WT MDSC，并在过继转移到WT小鼠时有效促进肿瘤生长。从机制上讲，PLCγ2−/− MDSC显示β-catenin水平降低，β-catenin表达的恢复降低了它们的扩增和肿瘤生长。与β-连环蛋白在MDSC中的负面作用一致，其在骨髓群体中的缺失导致MDSC积累并支持肿瘤进展，而组成型活性的β-连环蛋白的表达减少MDSC数量并防止肿瘤生长。进一步强调了这些发现的临床相关性，与健康对照相比，从胰腺癌患者中分离的MDSC显示出降低的p-PLCγ2和β-连环蛋白水平，与荷瘤小鼠相似。因此，我们首次证明PLCγ2-β-catenin通路的下调发生在小鼠和人类中，并导致MDSC介导的肿瘤扩张，引起了对全身性β-catenin阻断作为抗癌治疗的功效的关注。
Down-regulation of PLCγ2 and β-catenin signaling in tumor associated myeloid cells allows for their expansion and tumor growth in mice and humans. Myeloid-derived suppressor cells (MDSCs) favor tumor promotion, mainly by suppressing antitumor T cell responses in many cancers. Although the mechanism of T cell inhibition is established, the pathways leading to MDSC accumulation in bone marrow and secondary lymphoid organs of tumor-bearing hosts remain unclear. We demonstrate that down-regulation of PLCγ2 signaling in MDSCs is responsible for their aberrant expansion during tumor progression. PLCγ2−/− MDSCs show stronger immune-suppressive activity against CD8+ T cells than WT MDSCs and potently promote tumor growth when adoptively transferred into WT mice. Mechanistically, PLCγ2−/− MDSCs display reduced β-catenin levels, and restoration of β-catenin expression decreases their expansion and tumor growth. Consistent with a negative role for β-catenin in MDSCs, its deletion in the myeloid population leads to MDSC accumulation and supports tumor progression, whereas expression of β-catenin constitutively active reduces MDSC numbers and protects from tumor growth. Further emphasizing the clinical relevance of these findings, MDSCs isolated from pancreatic cancer patients show reduced p-PLCγ2 and β-catenin levels compared with healthy controls, similar to tumor-bearing mice. Thus, for the first time, we demonstrate that down-regulation of PLCγ2–β-catenin pathway occurs in mice and humans and leads to MDSC-mediated tumor expansion, raising concerns about the efficacy of systemic β-catenin blockade as anti-cancer therapy.
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