Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy.
Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy.
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DOI：
10.1158/2326-6066.cir-14-0167
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发表时间：
2015-09
影响因子：
10.1
通讯作者：
Hanks BA
中科院分区：
文献类型：
--
作者：
Holtzhausen A;Zhao F;Evans KS;Tsutsui M;Orabona C;Tyler DS;Hanks BA
β-catenin信号通路已被证明促进耐受性树突状细胞（DC）群体的发展，能够驱动调节性t细胞（Treg）分化。在临床前模型中，进一步的研究表明耐受性dc可促进癌变。这种DC人群建立免疫耐受的分子机制尚不清楚，发展中的癌症可以通过这种途径来破坏免疫监视的方法目前尚不清楚。这项研究表明，黑色素瘤衍生的Wnt5a配体通过局部dc以依赖于β-catenin信号通路的方式上调吲哚胺2,3-双加氧酶-1 （IDO）酶的持久表达和活性。这些数据表明，wnt5a条件下的dc以ido依赖的方式促进treg的分化，这一过程有助于抑制黑色素瘤的免疫监视。我们进一步表明，黑色素瘤Wnt配体分泌所必需的PORCN膜结合o -酰基转移酶的遗传沉默增强了抗肿瘤t细胞免疫，并且当与抗ctla -4抗体治疗联合使用时，该酶的药理学抑制协同抑制黑色素瘤的进展。最后，我们的数据表明，基于包括IDO在内的靶基因表达谱的β-catenin信号活性与黑色素瘤疾病负担和无进展生存期降低有关。这项工作暗示Wnt -β-catenin信号通路是黑色素瘤免疫微环境中的一个新的治疗靶点，并证明了操纵DC功能作为优化肿瘤免疫治疗策略的潜在影响。
The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane–bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti–CTLA-4 antibody therapy. Finally, our data suggest that β-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node–derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt–β-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy.