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PD-1参与增强小鼠抗肿瘤疫苗的效果

日期:2012年10月16日 浏览次数:4,333

出处:J Immunol. 2012 Sep 1;189(5):2338-47. Epub 2012 Jul 25.
作者:Mkrtichyan M, Najjar YG, Raulfs EC, Liu L, Langerman S, Guittard G, Ozbun L, Khleif SN.
单位:Cancer Vaccine Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

论文摘要:

重组CD273(B7-DC)-muIg通过交联PD-1(CD279)增强小鼠抗肿瘤免疫效果。

该重组蛋白可以通过两种机制增强抗肿瘤疫苗的效果:

1)它可以抑制PD-1high CD4+T 细胞增殖,因此导致肿瘤部位Treg细胞数量减少。
2)它可以减少已耗竭的CD8+T细胞数量,从而能发挥较好的特异的抗肿瘤细胞杀伤反应。

英文摘要:

Abstract

Programmed death receptor 1 (PD-1) is an important signaling molecule often involved in tumor-mediated suppression of activated immune cells. Binding of this receptor to its ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), attenuates T cell activation, reduces IL-2 and IFN-γ secretion, decreases proliferation and cytotoxicity, and induces apoptosis. B7-DC-Ig is a recombinant protein that binds and targets PD-1. It is composed of an extracellular domain of murine B7-DC fused to the Fc portion of murine IgG2a. In this study, we demonstrate that B7-DC-Ig can enhance the therapeutic efficacy of vaccine when combined with cyclophosphamide. We show that this combination significantly enhances Ag-specific immune responses and leads to complete eradication of established tumors in 60% of mice and that this effect is CD8 dependent. We identified a novel mechanism by which B7-DC-Ig exerts its therapeutic effect that is distinctly different from direct blocking of the PD-L1-PD-1 interaction. In this study, we demonstrate that there are significant differences between levels and timing of surface PD-1 expression on different T cell subsets. We found that these differences play critical roles in anti-tumor immune effect exhibited by B7-DC-Ig through inhibiting proliferation of PD-1(high) CD4 T cells, leading to a significant decrease in the level of these cells, which are enriched for regulatory T cells, within the tumor. In addition, it also leads to a decrease in PD-1(high) CD8 T cells, tipping the balance toward nonexhausted functional PD-1(low) CD8 T cells. We believe that the PD-1 expression level on T cells is a crucial factor that needs to be considered when designing PD-1-targeting immune therapies.

原文链接:http://www.ncbi.nlm.nih.gov/pubmed/22837483

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