I型组蛋白去乙酰化酶家族在肿瘤免疫原性调控中的作用及机制

The role of tumor immune therapy has been validated and immune therapy shows great promises in cancer treatment. Tumor immunogenicity underlies the basis of triggering anti-tumor immunity, of which the alteration would radically convert the type and intensity of immune response. Tumor-bearing mice which benefit from combinatorial therapy of checkpoint blockers and Entinostat, a class I specific.HDACs inhibitor, show boosted anti-tumor immune response. However, the most unclear question is that ‘what’s the role of HDACs on each of host immune system or tumor immunogenicity’. In this program, we focus on class I HDACs and use the means of CRISPR-CAS9 technology and tumor xenograft mouse model, combiningmechanism studies and clinical data analyses, targeting to elucidate roles of.HDACs on sustaining tumor immunogenicity through the following parts: 1. Effects of interference of HDACs’ activities on in vivo tumor growth; 2. Effects of HDACs knockout on tumor immunogenicity; 3. Clinical relevance of HDACs’ expression levels and patients’ survival; 4. Gene expression profiles and regulatory mechanisms; 5. Alterations of constitutions and functions of intra-tumoral immune cells. In conclusion, this program would enrich the studies on regulatory mechanisms of tumor immunogenicity, and provide scientific basis for applications of HDIs on immune therapy and theory basis for R&D of single HDAC-specific inhibitors.

肿瘤免疫疗法已被证实有效且极具应用前景。肿瘤免疫原性是抗肿瘤免疫应答发生的先决条件，其变化可从根本上改变免疫反应的类型和强度。小鼠模型中，PD-1抗体联用泛I型HDACs抑制剂（HDACi）Entinostat可增强抗肿瘤免疫应答并改善PD-1阻断治疗效果。尚不明确的是：HDACs对宿主免疫系统和肿瘤细胞免疫原性分别有何作用。本项目将聚焦于I型HDACs，利用基因敲除技术和小鼠移植瘤模型，结合机制研究和临床数据分析，系统研究：1. 抑制HDACs活性对小鼠移植瘤生长的影响；2. HDACs-KO对肿瘤免疫原性的影响；3. 肿瘤组织HDACs表达水平与病人生存的相关性；4. 基因表达变化及调节机制；5.免疫细胞组成和功能变化。本项目的实施，将丰富肿瘤免疫原性调节机制的研究，为HDACi用于免疫治疗提供科学依据，并为单体特异性HDACi的研发提供理论基础。

人们普遍认为组蛋白去乙酰化酶（HDACs）抑制剂作为一类新的抗癌药物，通过直接引起肿瘤细胞的细胞周期停滞和凋亡而发挥其抗肿瘤活性。然而，我们目前的研究表明，I 类 HDACs 抑制剂如 Entinostat 和 Panobinostat 可有效抑制免疫活性小鼠的肿瘤生长，但不能抑制免疫缺陷小鼠的肿瘤生长。对 Hdac1/2/3 敲除肿瘤细胞的进一步研究表明，HDAC3 的肿瘤特异性失活通过激活抗肿瘤免疫来抑制肿瘤生长。具体来说，我们发现 HDAC3 直接与启动子区域结合并抑制 CXCL9/10/11 趋化因子的表达。 Hdac3 缺陷型肿瘤细胞表达高水平的这些趋化因子，这些趋化因子通过将 CXCR3+ T 细胞募集到肿瘤微环境中来抑制免疫活性小鼠的肿瘤生长。因此，我们的研究提供了一种新的抗肿瘤机制，HDAC3抑制通过增强肿瘤微环境中的免疫细胞浸润来抑制肿瘤生长。