OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor
OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor
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DOI：
10.1158/0008-5472.can-07-6484
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发表时间：
2008-07-01
期刊：
影响因子：
11.2
通讯作者：
Weinberg, Andrew D.
中科院分区：
文献类型：
--
作者：
Gough, Michael J.;Ruby, Carl E.;Weinberg, Andrew D.
获得完整的T细胞效应子功能和记忆分化需要适当的共刺激信号，包括共刺激分子OX 40（TNFRSF 4，CD 134）的连接。尽管存在肿瘤特异性T细胞，肿瘤通常仍会生长，并建立一个具有弱共刺激和免疫抑制的环境。已显示给予0X 40激动剂显著增加荷瘤小鼠的存活，并且依赖于肿瘤特异性引发期间CD 4和CD 8 T细胞两者的存在。为了了解OX 40激动剂如何在已建立肿瘤的小鼠中起作用，我们开发了一种模型来研究肿瘤环境中免疫细胞群的变化。我们在此显示，全身施用0X 40激动剂抗体增加了三种不同肿瘤模型中肿瘤部位处的CD 8 T细胞的比例。通过施用0X 40激动性抗体，肿瘤部位处的CD 8 T细胞的功能也增加，并且我们观察到肿瘤内抗原特异性CD 8 T细胞的比例增加。尽管肿瘤部位的T调节细胞比例降低，但脾脏中的T调节细胞功能不受0X 40激动剂抗体治疗的影响。有趣的是，0X 40激动性抗体的施用引起肿瘤间质的显著变化，包括减少的巨噬细胞、髓源性抑制细胞和减少的转化生长因子-β的表达。因此，靶向OX 40的疗法通过增强CD 8 T细胞的浸润和功能以及减少肿瘤内的抑制性影响而显著改变了肿瘤环境。
Acquisition of full T-cell effector function and memory differentiation requires appropriate costimulatory signals, including ligation of the costimulatory molecule OX40 (TNFRSF4, CD134). Tumors often grow despite the presence of tumor-specific T cells and establish an environment with weak costimulation and immune suppression. Administration of OX40 agonists has been shown to significantly increase the survival of tumor-bearing mice and was dependent on the presence of both CD4 and CD8 T cells during tumor-specific priming. To understand how OX40 agonists work in mice with established tumors, we developed a model to study changes in immune cell populations within the tumor environment. We show here that systemic administration of OX40 agonist antibodies increased the proportion of CD8 T cells at the tumor site in three different tumor models. The function of the CD8 T cells at the tumor site was also increased by administration of OX40 agonist antibody, and we observed an increase in the proportion of antigen-specific CD8 T cells within the tumor. Despite decreases in the proportion of T regulatory cells at the tumor site, T regulatory cell function in the spleen was unaffected by OX40 agonist antibody therapy. Interestingly, administration of OX40 agonist antibody caused significant changes in the tumor stroma, including decreased macrophages, myeloid-derived suppressor cells, and decreased expression of transforming growth factor-beta. Thus, therapies targeting OX40 dramatically changed the tumor environment by enhancing the infiltration and function of CD8 T cells combined with diminished suppressive influences within the tumor.