期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 12, 页码 5549-5560出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI123360
关键词
-
资金
- National Institutes of Health [CA133085, CA182518, CA172105]
- Veterans Affairs award [BX001962]
- Intramural Research Program of the National Institute of Child Health and Human Development
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [ZIAHD001310] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [R01CA133085, R01CA182518, R01CA172105] Funding Source: NIH RePORTER
Despite breakthroughs in immune checkpoint inhibitor (ICI) immunotherapy, not all human cancers respond to ICI immunotherapy and a large fraction of patients with the responsive types of cancers do not respond to current ICI immunotherapy. This clinical conundrum suggests that additional immune checkpoints exist. We report here that interferon regulatory factor 8 (IRF8) deficiency led to impairment of cytotoxic T lymphocyte (CTL) activation and allograft tumor tolerance. However, analysis of chimera mice with competitive reconstitution of WT and IRF8-KO bone marrow cells as well as mice with IRF8 deficiency only in T cells indicated that IRF8 plays no intrinsic role in CTL activation. Instead, IRF8 functioned as a repressor of osteopontin (OPN), the physiological ligand for CD44 on T cells, in CD11b(+)Ly6C(lo)Ly6G(+) myeloid cells and OPN acted as a potent T cell suppressor. IRF8 bound to the Spp1 promoter to repress OPN expression in colon epithelial cells, and colon carcinoma exhibited decreased IRF8 and increased OPN expression. The elevated expression of OPN in human colon carcinoma was correlated with decreased patient survival. Our data indicate that myeloid and tumor cell-expressed OPN acts as an immune checkpoint to suppress T cell activation and confer host tumor immune tolerance.
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