Immune Tolerance to Tumor Antigens Occurs in a Specialized Environment of the Spleen
Immune Tolerance to Tumor Antigens Occurs in a Specialized Environment of the Spleen
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DOI：
10.1016/j.celrep.2012.08.006
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发表时间：
2012-09-01
期刊：
影响因子：
8.8
通讯作者：
Bronte, Vincenzo
中科院分区：
文献类型：
--
作者：
Ugel, Stefano;Peranzoni, Elisa;Bronte, Vincenzo
外周对肿瘤抗原的耐受性(AGS)是抗肿瘤免疫的主要障碍。引流淋巴结被认为是将抗原提呈给T细胞和外周耐受开始的特权部位。在这里，我们证明了脾在肿瘤诱导的耐受中起着至关重要的作用。脾切除可恢复淋巴细胞功能，并在配合免疫治疗时可导致肿瘤消退。脾CD11b(+)、Gr-1(Int)、Ly6C(Hi)细胞主要由增殖的CCR2(+)炎性单核细胞组成，具有髓系祖细胞的特征，在脾的边缘区域扩张。在这里，它们改变了正常组织的细胞结构，并与记忆CD8(+)T细胞密切相关，交叉呈现肿瘤AGS并导致它们的耐受。由于其高增殖能力，该髓系细胞亚群对低剂量化疗也很敏感，可以作为被动免疫治疗的辅助手段。癌症患者的CCL2血清水平与未成熟髓系细胞的积累直接相关，并可预测对癌症疫苗产生多肽反应的患者的总存活率。
Peripheral tolerance to tumor antigens (Ags) is a major hurdle for antitumor immunity. Draining lymph nodes are considered the privileged sites for Ag presentation to T cells and for the onset of peripheral tolerance. Here, we show that the spleen is fundamentally important for tumor-induced tolerance. Splenectomy restores lymphocyte function and induces tumor regression when coupled with immunotherapy. Splenic CD11b(+)Gr-1(int)Ly6C(hi) cells, mostly comprising proliferating CCR2(+)-inflammatory monocytes with features of myeloid progenitors, expand in the marginal zone of the spleen. Here, they alter the normal tissue cytoarchitecture and closely associate with memory CD8(+) T cells, cross-presenting tumor Ags and causing their tolerization. Because of its high proliferative potential, this myeloid cell subset is also susceptible to low-dose chemotherapy, which can be exploited as an adjuvant to passive immunotherapy. CCL2 serum levels in cancer patients are directly related to the accumulation of immature myeloid cells and are predictive for overall survival in patients who develop a multipeptide response to cancer vaccines.