期刊
CANCER RESEARCH
卷 74, 期 19, 页码 5458-5468出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-1258
关键词
-
类别
资金
- MedImmune and Cancer Research UK
- MRC [G0500366] Funding Source: UKRI
- Cancer Research UK [17737, 11335, 16397] Funding Source: researchfish
- Medical Research Council [G0500366] Funding Source: researchfish
Radiotherapy is a major part in the treatment of most common cancers, but many patients experience local recurrence with metastatic disease. In evaluating response biomarkers, we found that low doses of fractionated radiotherapy led to PD-L1 upregulation on tumor cells in a variety of syngeneic mouse models of cancer. Notably, fractionated radiotherapy delivered in combination with alpha PD-1 or alpha PD-L1 mAbs generated efficacious CD8(+) T-cell responses that improved local tumor control, long-term survival, and protection against tumor rechallenge. These favorable outcomes were associated with induction of a tumor antigen-specific memory immune response. Mechanistic investigations showed that IFN gamma produced by CD8(+) T cells was responsible for mediating PD-L1 upregulation on tumor cells after delivery of fractionated radiotherapy. Scheduling of anti-PD-L1 mAb was important for therapeutic outcome, with concomitant but not sequential administration with fractionated radiotherapy required to improve survival. Taken together, our results reveal the mechanistic basis for an adaptive response by tumor cells that mediates resistance to fractionated radiotherapy and its treatment failure. With attention to scheduling, combination immunoradiotherapy with radiotherapy and PD-1/PD-L1 signaling blockade may offer an immediate strategy for clinical evaluation to improve treatment outcomes. (C) 2014 AACR.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据