H3K9甲基化酶SETDB1表观抑制头颈鳞癌I型干扰素应答和CD8阳性T细胞抗肿瘤免疫效应的分子机制

CD8+T细胞在抗肿瘤免疫应答中具有重要作用。我们发现SETDB1敲除后：头颈鳞癌组织浸润性CD8+T细胞的抗肿瘤免疫效应增强；干扰素IFN-β的表达升高；内源性逆转录病毒（ERVs）活化并导致胞浆dsRNA蓄积；头颈鳞癌细胞内可能存在SETDB1/ERVs/MDA5/MAVS/IRFs/IFN-β通路。据此推测SETDB1敲除可降低H3K9me3水平，活化ERVs导致胞浆dsRNA蓄积并经MDA5/MAVS/IRFs通路启动IFN-β干扰素应答，最终增强头颈鳞癌组织浸润性CD8+T细胞的抗肿瘤免疫效应。为此，本项目将通过体内外实验证实上述通路可作为衔接肿瘤细胞与CD8+T细胞的“分子桥梁”，调控组织浸润性CD8+T细胞抗肿瘤免疫效应；重点阐明该通路的内在调控机制并证实其临床价值；找寻与头颈鳞癌免疫抑制密切相关的分子标志物和治疗靶点，为搭建头颈鳞癌免疫分子分型标准指导免疫治疗奠定研究基础。

CD8+T cell functions importantly in antitumor immune response. Our previous data indicated that SETDB1 knockout (KO) enhanced the anti-tumor immunity of tissue infiltrating CD8+ T cell in squamous cell carcinoma of the head and neck (SCCHN), which was accompanied by increased expression of IFN-β and activated transcription of endogenous retrovirus (ERVs) that leading to accumulation of double strand RNA (dsRNA). Moreover, a potential SETDB1/ERVs/MDA5/MAVS/IRFs/ IFN-β signaling pathway may exist in SCCHN cells. Therefore, we hypothesize that SETDB1 KO induces the transcription of ERVs and cytoplasmic accumulation of dsRNA, which in turn initiates IFN-β interferon response via MDA5/MAVS/IRFs signaling pathway and finally strengthens the anti-tumor immunity of CD8+ T cells in SCCHN. To confirm this hypothesis, both in vitro and in vivo experiments will be performed to observe whether the signaling pathway can function as a molecular bridge to modulate the mutual communication of SCCHN cells and CD8+ T cells, which participates in IFN-β mediated anti-tumor immune response of CD8+T cells in SCCHN. In this program, we will focus on the intrinsic molecular regulatory mechanisms of this signaling pathway in SCCHN cells. Finally, the clinical relevance of molecules in this signaling pathway will be investigated in a large SCCHN specimens with intact clinical information. The success of this program will accelerate the discovery of molecular biomarkers associated with SCCHN immunosuppression and identify potential molecular targets to reverse immunosuppression, which will pave new way for the establishment of novel immunomolecular system and immunotherapy in patients with SCCHN.