Generation of antigen-presenting cells from tumor-infiltrated CD11b myeloid cells with DNA demethylating agent 5-aza-2'-deoxycytidine
Generation of antigen-presenting cells from tumor-infiltrated CD11b myeloid cells with DNA demethylating agent 5-aza-2'-deoxycytidine
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DOI：
10.1007/s00262-009-0786-4
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发表时间：
2010-05-01
影响因子：
5.8
通讯作者：
Kusmartsev, Sergei
中科院分区：
文献类型：
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作者：
Daurkin, Irina;Eruslanov, Evgeniy;Kusmartsev, Sergei
肿瘤募集的CD 11b骨髓细胞，包括骨髓来源的抑制细胞，在肿瘤进展中发挥重要作用，因为这些细胞参与肿瘤诱导的免疫抑制和肿瘤新生血管发生。另一方面，肿瘤浸润的CD 11b骨髓细胞可能是免疫刺激性抗原呈递细胞（APC）的来源，因为这些细胞中的大多数代表树突状细胞和巨噬细胞的共同前体。在这里，我们研究了从肿瘤浸润的CD 11b骨髓细胞产生成熟APC的可能性。我们证明，在体外将新鲜切除的小鼠肿瘤暴露于DNA甲基转移酶抑制剂5-氮杂-2 '-脱氧胞苷（地西他滨，AZA）导致肿瘤细胞的选择性消除，但令人惊讶的是，它也富集了CD 45（+）肿瘤浸润细胞。大多数“AZA后”存活的CD 45（+）肿瘤浸润细胞以CD 11b髓样细胞为代表。在AZA和GM-CSF存在下培养分离的肿瘤浸润的CD 11b细胞促进其分化为成熟的F4/80/CD 11 c/MHC II类阳性APC。这些肿瘤源性骨髓APC产生的免疫抑制（IL-13，IL-10，PGE（2）），促血管生成（VEGF，MMP-9）和促炎（IL-1 β，IL-6，MIP-2）介质的量比其前体，新鲜分离的肿瘤浸润的CD 11b细胞显著减少。用离体产生的肿瘤来源的APC接种未处理小鼠导致70%的小鼠免于肿瘤生长。重要的是，不需要负载外源性抗原的肿瘤来源的APC来刺激T细胞应答并诱导抗肿瘤效应。总的来说，我们的结果首次证明，肿瘤浸润的CD 11b髓样细胞可以在DNA去甲基化剂5-aza-2 '-deoxycytidine的存在下富集和分化为成熟的肿瘤源性APC，其可以用于癌症免疫治疗。
Tumor-recruited CD11b myeloid cells, including myeloid-derived suppressor cells, play a significant role in tumor progression, as these cells are involved in tumor-induced immune suppression and tumor neovasculogenesis. On the other hand, the tumor-infiltrated CD11b myeloid cells could potentially be a source of immunostimulatory antigen-presenting cells (APCs), since most of these cells represent common precursors of both dendritic cells and macrophages. Here, we investigated the possibility of generating mature APCs from tumor-infiltrated CD11b myeloid cells. We demonstrate that in vitro exposure of freshly excised mouse tumors to DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (decitabine, AZA) results in selective elimination of tumor cells, but, surprisingly it also enriches CD45(+) tumor-infiltrated cells. The majority of "post-AZA" surviving CD45(+) tumor-infiltrated cells were represented by CD11b myeloid cells. A culture of isolated tumor-infiltrated CD11b cells in the presence of AZA and GM-CSF promoted their differentiation into mature F4/80/CD11c/MHC class II-positive APCs. These tumor-derived myeloid APCs produced substantially reduced amounts of immunosuppressive (IL-13, IL-10, PGE(2)), pro-angiogenic (VEGF, MMP-9) and pro-inflammatory (IL-1beta, IL-6, MIP-2) mediators than their precursors, freshly isolated tumor-infiltrated CD11b cells. Vaccinating na < ve mice with ex vivo generated tumor-derived APCs resulted in the protection of 70% mice from tumor outgrowth. Importantly, no loading of tumor-derived APC with exogenous antigen was needed to stimulate T cell response and induce the anti-tumor effect. Collectively, our results for the first time demonstrate that tumor-infiltrated CD11b myeloid cells can be enriched and differentiated in the presence of DNA demethylating agent 5-aza-2'-deoxycytidine into mature tumor-derived APCs, which could be used for cancer immunotherapy.