期刊
CANCER RESEARCH
卷 78, 期 5, 页码 1275-1292出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-1833
关键词
-
类别
资金
- Cancer Research UK [A15115]
- Medical Research Council (MRC) [MR/L005069/1]
- Bloodwise project grant [15003]
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [1432, 5172, 15585]
- MIUR PRIN grant [2009EWAW4M_003]
- MIUR FIRB grant [RBA-P10A9H9]
- L'Aquila University PhD program in Experimental Medicine
- L'Aquila University PhD program in Biotechnology
- NATIONAL CANCER INSTITUTE [R01CA098583, R01CA084040] Funding Source: NIH RePORTER
- Cancer Research UK [15115] Funding Source: researchfish
- Medical Research Council [MR/L005069/1] Funding Source: researchfish
- MRC [MR/L005069/1] Funding Source: UKRI
T-cell exclusion from the tumor microenvironment (TME) is a major barrier to overcoming immune escape. Here, we identify a myeloid-intrinsic mechanism governed by the NF-kappa B effector molecule GADD45 beta that restricts tumor-associated inflammation and T-cell trafficking into tumors. In various models of solid cancers refractory to immunotherapies, including hepatocellular carcinoma and ovarian adenocarcinoma, Gadd45 beta inhibition in myeloid cells restored activation of proinflammatory tumor-associated macrophages (TAM) and intratumoral immune infiltration, thereby diminishing oncogenesis. Our results provide a basis to interpret clinical evidence that elevated expression of GADD45B confers poor clinical outcomes in most human cancers. Furthermore, they suggest a therapeutic target in GADD45 beta for reprogramming TAM to overcome immunosuppression and T-cell exclusion from the TME. Significance: These findings define a myeloid-based immune checkpoint that restricts T-cell trafficking into tumors, with potentially important therapeutic implications to generally improve the efficacy of cancer immunotherapy. (C) 2017 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