Antitumor monoclonal antibodies enhance cross-presentation of cellular antigens and the generation of myeloma-specific kill T cells dentritic cells
Antitumor monoclonal antibodies enhance cross-presentation of cellular antigens and the generation of myeloma-specific kill T cells dentritic cells
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DOI：
10.1084/jem.20011097
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发表时间：
2002-01-07
影响因子：
15.3
通讯作者：
Dhodapkar, MV
中科院分区：
文献类型：
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作者：
Dhodapkar, KM;Krasovsky, J;Dhodapkar, MV
单克隆抗体（mAb）的抗肿瘤作用机制尚未完全了解。在这里，我们表明，用抗多配体蛋白聚糖-1抗体包被骨髓瘤细胞促进树突状细胞（DC）向来自健康供体的自体T细胞交叉呈递细胞抗原。将用抗多配体蛋白聚糖-1或同种型匹配的对照抗体处理的肿瘤细胞喂给HLA错配的单核细胞衍生的未成熟DC。肿瘤细胞负载的成熟DC诱导了强烈的CD 8（+）T细胞应答，该应答对肿瘤中表达的癌-睾丸（C-T）抗原具有特异性。CD 8（+）T细胞杀死肽脉冲靶点，以及骨髓瘤肿瘤细胞。重要的是，单克隆抗体包被的肿瘤负载的DC始终上级于负载肽或死亡细胞的DC，以引发肿瘤特异性杀伤T细胞。这种增强的交叉呈递不是由于增强的肿瘤细胞摄取或DC成熟。当NY-Eso-1阳性和阴性骨髓瘤细胞的混合物被DC捕获时，抗多配体蛋白聚糖-1抗体必须在NY-Eso-1阳性细胞上以引发NY-Eso-1特异性应答。通过用Fc γ受体阻断抗体预处理DC来抑制交叉呈递。将mAb包被的肿瘤靶向DC可能有助于肿瘤反应性mAb的疗效，并为免疫治疗提供了新的策略。
The mechanism of antitumor effect of monoclonal antibodies (mAbs) is not fully understood. Here we show that coating myeloma cells with anti-syndecan-1 antibody promotes cross-presentation of cellular antigens by dendritic cells (DCs) to autologous T cells from healthy donors. The tumor cells treated with anti-syndecan-1 or isotype-matched control antibody were fed to HLA-mismatched monocyte-derived immature DCs. Tumor cell-loaded mature DCs induced a strong CD8(+) T cell response that was specific for the cancer-testis (C-T) antigens expressed in the tumor. The CD8(+) T cells killed peptide-pulsed targets, as well as myeloma tumor cells. Importantly, mAbs-coated tumor-loaded DCs were consistently superior to DCs loaded with peptides or dying cells for eliciting tumor-specific killer T cells. This enhanced cross-presentation was not due to enhanced tumor cell uptake or to DC maturation. When mixtures of NY-Eso-1-positive and -negative myeloma cells were captured by DCs, the anti-syndecan-1 antibody had to be on the NY-Eso-1-positive cells to elicit NY-Eso-1-specific response. Cross-presentation was inhibited by pretreatment of DCs with Fcgamma receptor blocking antibodies. Targeting of mAb-coated tumors to DCs may contribute to the efficacy of tumor-reactive mAb and offers a new strategy for immunotherapy.