Heat-Shock Induction of Tumor-Derived Danger Signals Mediates Rapid Monocyte Differentiation into Clinically Effective Dendritic Cells
Heat-Shock Induction of Tumor-Derived Danger Signals Mediates Rapid Monocyte Differentiation into Clinically Effective Dendritic Cells
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DOI：
10.1158/1078-0432.ccr-10-2384
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发表时间：
2011-04-15
影响因子：
11.5
通讯作者：
Salazar-Onfray, Flavio
中科院分区：
文献类型：
--
作者：
Aguilera, Raquel;Saffie, Carlos;Salazar-Onfray, Flavio
目的：本研究从生物学和临床上描述了一种新型的树突状细胞（DC），这种树突状细胞在短期内产生，称为肿瘤抗原呈递细胞（TAPCells）。特别是，我们鉴定了来自热休克同种异体黑色素瘤细胞（TRIMEL）的裂解物中存在的因子，这些因子与TAP细胞在体外和接种疫苗的黑色素瘤患者中诱导CD 8（+）T细胞应答的增强能力相关。首先，对TAP细胞进行了广泛的表型和功能表征，随后在2个月的时间内用四个剂量的TAP细胞接种45名黑素瘤患者。治疗后分析特异性迟发型超敏反应（DTH），并与总生存率相关。结果：TRIMEL诱导TAP细胞分化为成熟DC样表型，并有效激活黑色素瘤特异性CD 4（+）和CD 8（+）T细胞。在临床上，64%的接种疫苗的患者对TRIMEL表现出阳性DTH反应，这与总生存率的提高有关。HS处理的肿瘤细胞增加钙网蛋白（CRT）质膜易位，并诱导高迁移率族蛋白1（HMGB 1）的释放。CRT和HMGB 1动员分别与增强的TAP细胞成熟和抗原（Ag）交叉呈递相关。DTH浸润分析显示存在CD 8（+）/CD 45 RO（+）T细胞，从而证实了TAP细胞在体内交叉提呈Ag的能力。结论：我们的结果表明，来自热休克肿瘤细胞的裂解物是肿瘤相关Ag的最佳来源，这对于产生具有改善的Ag交叉提呈能力和临床有效免疫原性的DC至关重要。临床癌症研究; 17（8）; 2474-83。(C)2011年AACR。
Purpose: This study characterizes, biologically and clinically, a novel type of dendritic cells (DC) produced in the short term and called tumor antigen-presenting cells (TAPCells). In particular, we identified factors present in a lysate derived from heat-shocked allogeneic melanoma cells (TRIMEL) that are associated with TAPCells' enhanced capability to induce CD8(+) T-cell responses in vitro and in vaccinated melanoma patients.Experimental Design: First, extensive phenotypic and functional characterization of TAPCells was performed, followed by vaccination of 45 melanoma patients with four doses of TAPCells over a period of 2 months. Specific delayed-type hypersensitivity (DTH) reaction was analyzed posttreatment and correlated with overall survival rates. Furthermore, heat-shock (HS)-induced factors present in TRIMEL and their effects on DC activation were identified and studied.Results: TRIMEL induced a committed, mature, DC-like phenotype in TAPCells and effectively activated melanoma-specific CD4(+) and CD8(+) T cells. Clinically, 64% of vaccinated patients showed positive DTH reaction against TRIMEL, and this was associated with improved overall survival. HS treatment of tumor cells increased calreticulin (CRT) plasma membrane translocation and induced the release of high-mobility group box 1 proteins (HMGB1). Both CRT and HMGB1 mobilization were associated with enhanced TAPCells' maturation and antigen (Ag) cross-presentation, respectively. DTH infiltration analysis revealed the presence of CD8(+)/CD45RO(+) T cells, thus confirming TAPCells' ability to cross-present Ags in vivo.Conclusions: Our results indicate that lysates derived fromheat-shocked tumor cells are an optimal source of tumor-associated Ags, which are crucial for the generation of DCs with improved Ag cross-presentation capacity and clinically effective immunogenicity. Clin Cancer Res; 17(8); 2474-83. (C) 2011 AACR.