Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy.
Cell Rep. 2012 Sep 27;2(3):628-39. doi: 10.1016/j.celrep.2012.08.006. Epub 2012 Sep 6.
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.
肿瘤抗原（Ags）的外周耐受是抗肿瘤免疫的主要障碍。引流淋巴结被认为是抗原呈递给 T 细胞和外周耐受发生的特化部位。在这里，我们表明脾脏对于肿瘤诱导的耐受至关重要。脾切除术与免疫疗法结合使用时可恢复淋巴细胞功能并诱导肿瘤消退。脾脏 CD11b(+)Gr-1(int)Ly6C(hi) 细胞主要由增殖的 CCR2(+)-炎性单核细胞组成，具有髓系前体细胞的特征，在脾脏的边缘区扩增。在这里，它们改变正常的组织细胞结构，并与记忆 CD8(+)T 细胞密切相关，交叉呈递肿瘤 Ag 并导致其耐受。由于其高增殖潜能，这个髓样细胞亚群也容易受到低剂量化疗的影响，可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样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生存率。
