肿瘤微环境
免疫疗法
癌症研究
封锁
癌症免疫疗法
胰腺癌
免疫系统
细胞毒性T细胞
髓样
免疫检查点
生物
PD-L1
髓源性抑制细胞
免疫学
T细胞
癌症
癌细胞
肿瘤浸润淋巴细胞
医学
受体
抑制器
内科学
生物化学
遗传学
体外
作者
Yu Zhu,Brett L. Knolhoff,Melissa A. Meyer,Timothy M. Nywening,Brian L. West,Jingqin Luo,Andrea Wang‐Gillam,S. Peter Goedegebuure,David C. Linehan,David G. DeNardo
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2014-09-14
卷期号:74 (18): 5057-5069
被引量:955
标识
DOI:10.1158/0008-5472.can-13-3723
摘要
Abstract Cancer immunotherapy generally offers limited clinical benefit without coordinated strategies to mitigate the immunosuppressive nature of the tumor microenvironment. Critical drivers of immune escape in the tumor microenvironment include tumor-associated macrophages and myeloid-derived suppressor cells, which not only mediate immune suppression, but also promote metastatic dissemination and impart resistance to cytotoxic therapies. Thus, strategies to ablate the effects of these myeloid cell populations may offer great therapeutic potential. In this report, we demonstrate in a mouse model of pancreatic ductal adenocarcinoma (PDAC) that inhibiting signaling by the myeloid growth factor receptor CSF1R can functionally reprogram macrophage responses that enhance antigen presentation and productive antitumor T-cell responses. Investigations of this response revealed that CSF1R blockade also upregulated T-cell checkpoint molecules, including PDL1 and CTLA4, thereby restraining beneficial therapeutic effects. We found that PD1 and CTLA4 antagonists showed limited efficacy as single agents to restrain PDAC growth, but that combining these agents with CSF1R blockade potently elicited tumor regressions, even in larger established tumors. Taken together, our findings provide a rationale to reprogram immunosuppressive myeloid cell populations in the tumor microenvironment under conditions that can significantly empower the therapeutic effects of checkpoint-based immunotherapeutics. Cancer Res; 74(18); 5057–69. ©2014 AACR.
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