Institute of Biomedical Sciences, Faculty of Medicine, Clinical Hospital, University of Chile, Santiago, Chile.
Clin Cancer Res. 2011 Apr 15;17(8):2474-83. doi: 10.1158/1078-0432.CCR-10-2384. Epub 2011 Feb 3.
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.
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.
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.
Our results indicate that lysates derived from heat-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.
本研究对一种新型树突状细胞（DC）进行了生物学和临床特征分析，这种细胞在短期内产生，并被称为肿瘤抗原呈递细胞（TAPCells）。特别是，我们鉴定了热休克同种异体黑素瘤细胞（TRIMEL）裂解物中存在的与 TAPCells 体外和接种黑素瘤患者中增强 CD8+T 细胞反应能力相关的因子。
首先，对 TAPCells 进行了广泛的表型和功能特征分析，随后对 45 名黑素瘤患者进行了为期 2 个月的四次 TAPCells 接种疫苗。治疗后分析了特定的迟发型超敏（DTH）反应，并与总生存率相关联。此外，鉴定了 TRIMEL 中存在的热休克（HS）诱导因子及其对 DC 激活的影响，并进行了研究。
TRIMEL 在 TAPCells 中诱导出一种定型、成熟、类似 DC 的表型，并有效激活了黑素瘤特异性 CD4+和 CD8+T 细胞。临床上，64%的接种患者对 TRIMEL 表现出阳性 DTH 反应，这与总生存率的提高相关。肿瘤细胞的 HS 处理增加了钙网蛋白（CRT）的质膜易位，并诱导了高迁移率族 box1 蛋白（HMGB1）的释放。CRT 和 HMGB1 的动员分别与 TAPCells 的成熟和抗原（Ag）交叉呈递能力的增强相关。DTH 浸润分析显示存在 CD8+/CD45RO+T 细胞，从而证实了 TAPCells 在体内进行 Ag 交叉呈递的能力。
我们的结果表明，热休克肿瘤细胞的裂解物是肿瘤相关 Ag 的最佳来源，这对于产生具有增强 Ag 交叉呈递能力和临床有效免疫原性的 DC 至关重要。
