生物
癌症研究
PD-L1
免疫系统
癌症免疫疗法
CD8型
癌细胞
内部收益率1
T细胞
肿瘤微环境
结直肠癌
免疫疗法
癌症
免疫学
转录因子
基因
生物化学
遗传学
作者
Qiang Chen,Shuqing Zhuang,Yilin Hong,Lu Yang,Peng Guo,Pingli Mo,Kesong Peng,Wengang Li,Nengming Xiao,Chundong Yu
出处
期刊:Oncogene
[Springer Nature]
日期:2022-01-14
卷期号:41 (10): 1421-1433
被引量:17
标识
DOI:10.1038/s41388-021-02173-x
摘要
Programmed death-ligand 1 (PD-L1) is an important immunosuppressive molecule highly expressed on the surface of cancer cells. IFNγ triggered cancer cell immunosuppression against CD8+ T cell surveillance via up-regulation of PD-L1. Histone demethylase JMJD2D promotes colorectal cancer (CRC) progression; however, the role of JMJD2D in cancer immune escape is unknown. Here, we report that both PD-L1 and JMJD2D are frequently overexpressed in human CRC specimens with a significant positive correlation. Genetic ablation of JMJD2D in CRC cells attenuated the expression of PD-L1 and stalled tumor growth in mice, accompanied by the elevated number and effector function of tumor infiltrating CD8+ T cells. Mechanistically, JMJD2D coactivated SP-1 to promote the expression of IFNGR1, which elevated STAT3-IRF1 signaling and promoted PD-L1 expression. Again, JMJD2D is a major coactivator for STAT3-IRF1 axis to enhance PD-L1 transcription in a demethylation activity dependent manner. Furthermore, pharmacological inhibition of JMJD2D conduced to improve the anti-tumor efficacy of PD-L1 antibody as demonstrated by slower tumor growth and higher infiltration and function of CD8+ T cells in the combination of JMJD2D inhibitor 5-c-8HQ and PD-L1 antibody group compared with monotherapy with either agent. These results demonstrate that JMJD2D promotes CRC immune escape by enhancing PD-L1 expression to inhibit the activation and tumor infiltration of CD8+ T cells; targeting JMJD2D has the potential role in promoting the efficacy of anti-PD-1/PD-L1 immunotherapy.
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