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