CTLA4 blockade maximizes antitumor T-cell activation by dendritic cells presenting idiotype protein or opsonized anti-CD20 antibody-coated lymphoma cells
CTLA4 blockade maximizes antitumor T-cell activation by dendritic cells presenting idiotype protein or opsonized anti-CD20 antibody-coated lymphoma cells
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DOI：
10.1097/00002371-200211000-00002
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发表时间：
2002-11-01
影响因子：
3.9
通讯作者：
Komarovskaya, M
中科院分区：
文献类型：
--
作者：
Hsu, FJ;Komarovskaya, M
CTLA4是CD28刺激T细胞和137刺激树突状细胞(DC)共同刺激信号的负调节因子。针对CTLA4的抗体可以阻断其功能，并增加准备识别抗原的T细胞的激活。检测CTLA4阻断对DC与T细胞交叉提呈肿瘤抗原的影响。从接受独特型蛋白冲击的DC疫苗的患者中收集免疫T细胞和DC前体，暴露于抗原中，并通过流式细胞仪检测细胞内细胞因子的产生来检查抗肿瘤活性。独特型特异性激活发生在CD8(+)和CD4(+)T细胞群体中，并且在CTLA4阻断后高达58倍。这些T细胞能快速扩增并维持对肿瘤细胞的杀伤活性。然后检测T细胞对全肿瘤细胞致敏的DC的反应。树突状细胞含有Fc受体，包被调理抗CD20抗体后，能有效地吞噬淋巴瘤细胞。在几个小时内，DC吞噬肿瘤细胞，并在细胞质中观察到标记蛋白。当抗CD20抗体包被的肿瘤致敏的DC与CTLA4阻断联合使用时，ID特异性CD8(+)细胞的激活倍数高达15倍，而CD4(+)T细胞的激活倍数高达3倍。因此，阻断CTLA4可以增强对抗原特异性T细胞反应的测量和T细胞的扩增，用于临床研究。此外，CTLA4阻断和肿瘤抗体靶向DC的结合是一种有效的肿瘤细胞抗原交叉提呈方法。
CTLA4 is a negative regulator of the costimulatory signals induced by the interaction of CD28 on T cells and 137 on dendritic cells (DCs). Antibodies (Abs) against CTLA4 can block its function and increase the activation of T cells primed to recognize antigens. The effect of CTLA4 blockade on the cross-presentation of tumor antigens by DCs to T cells was examined. Immune T cells and DC precursors were collected from patients receiving idiotype protein-pulsed DC vaccines, exposed to antigen, and examined for antitumor activity by measuring intracellular cytokine production by FACS. Idiotype-specific activation occurred in CD8(+) and CD4(+) T-cell populations and was up to 58 fold higher with CTLA4 blockade. These T cells could be expanded quickly and maintained tumor cytolytic activity. T-cell responses to whole tumor cell-pulsed DCs were then examined. DCs contain Fc receptors and efficiently phagocytose lymphoma cells when coated with opsonizing anti-CD20 Abs. Within a few hours, DCs ingested tumor cells and labeled proteins were observed in the cytoplasm. When anti-CD20 Ab-coated tumor-pulsed DCs were used in combination with CTLA4 blockade, up to 15 fold higher activation of Id-specific CD8(+) and 3 fold higher CD4(+) T cells resulted. Thus, CTLA4 blockade can enhance the measurement of Ag-specific T-cell responses and the expansion of T cells for clinical studies. In addition, the combination of CTLA4 blockade and Ab targeting of tumor to DCs is an effective method for the cross-presentation of tumor cell antigens.