Immune checkpoint blockade reveals the stimulatory capacity of tumor-associated CD103+ dendritic cells in late-stage ovarian cancer
Immune checkpoint blockade reveals the stimulatory capacity of tumor-associated CD103+ dendritic cells in late-stage ovarian cancer
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DOI：
10.1080/2162402x.2016.1185583
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Adams, Sarah F.
中科院分区：
文献类型：
--
作者：
Flies, Dallas B.;Higuchi, Tomoe;Adams, Sarah F.
尽管卵巢癌中的免疫浸润与生存率提高相关，但卵巢肿瘤环境已被表征为免疫抑制，部分原因是随着疾病进展树突状细胞之间的功能转变。我们假设，树突状细胞亚群的流动与癌症进展负责观察到的抗肿瘤免疫反应的早期和晚期疾病的差异。在这里，我们确定了三个树突状细胞亚群在卵巢肿瘤环境中具有不同的功能。CD 11 c + CCD 11b（-）CD 103（+）树突状细胞在健康小鼠的腹腔中不存在，但在荷瘤小鼠中占树突状细胞的40%，并在晚期疾病中保留T细胞刺激能力。在CD 11 c + CCD 11b（+）细胞中，Lair-1表达区分刺激性和免疫调节性DC亚群，这些亚群也在肿瘤环境中富集。值得注意的是，PD-L1由Lair-1（hi）免疫调节树突状细胞表达，并可能导致局部肿瘤抗原特异性T细胞功能障碍。使用过继转移模型，我们发现PD-1阻断能够使肿瘤相关的CD 103（+）树突状细胞促进疾病清除。这些数据表明，随着癌症进展，在肿瘤环境中的局部树突状细胞亚群中维持抗肿瘤免疫能力。类似的树突状细胞亚群存在于卵巢癌妇女的恶性腹水中，支持这些结果的翻译相关性。
Although immune infiltrates in ovarian cancer are associated with improved survival, the ovarian tumor environment has been characterized as immunosuppressive, due in part to functional shifts among dendritic cells with disease progression. We hypothesized that flux in dendritic cell subpopulations with cancer progression were responsible for observed differences in antitumor immune responses in early and late-stage disease. Here we identify three dendritic cell subsets with disparate functions in the ovarian tumor environment. CD11c+CCD11b(-) CD103(+) dendritic cells are absent in the peritoneal cavity of healthy mice but comprise up to 40% of dendritic cells in tumor-bearing mice and retain T cell stimulatory capacity in advanced disease. Among CD11c+CCD11b(+) cells, Lair-1 expression distinguishes stimulatory and immunoregulatory DC subsets, which are also enriched in the tumor environment. Notably, PD-L1 is expressed by Lair-1(hi) immunoregulatory dendritic cells, and may contribute to local tumor antigen-specific T cell dysfunction. Using an adoptive transfer model, we find that PD-1 blockade enables tumor-associated CD103(+) dendritic cells to promote disease clearance. These data demonstrate that antitumor immune capacity is maintained among local dendritic cell subpopulations in the tumor environment with cancer progression. Similar dendritic cell subsets are present in malignant ascites from women with ovarian cancer, supporting the translational relevance of these results.