Objective Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by its lethality and limited treatment options, including the utilisation of checkpoint blockade (ICB) immunotherapy. Epigenetic dysregulation is a defining feature of tumourigenesis that is implicated in immune surveillance, but remains elusive in PDAC. Design To identify the factors that modulate immune surveillance, we employed in vivo epigenetic-focused CRISPR-Cas9 screen in mouse PDAC tumour models engrafted in either immunocompetent or immunodeficient mice. Results Here, we identified MED12 as a top hit, emerging as a potent negative modulator of immune tumour microenviroment (TME) in PDAC. Loss of Med12 significantly promoted infiltration and cytotoxicity of immune cells including CD8+ T cells, natural killer (NK) and NK1.1+ T cells in tumours, thereby heightening the sensitivity of ICB treatment in a mouse model of PDAC. Mechanistically, MED12 stabilised heterochromatin protein HP1A to repress H3K9me3-marked endogenous retroelements. The derepression of retrotransposons induced by MED12 loss triggered cytosolic nucleic acid sensing and subsequent activation of type I interferon pathways, ultimately leading to robust inflamed TME . Moreover, we uncovered a negative correlation between MED12 expression and immune resposne pathways, retrotransposon levels as well as the prognosis of patients with PDAC undergoing ICB therapy. Conclusion In summary, our findings underscore the pivotal role of MED12 in remodelling immnue TME through the epigenetic silencing of retrotransposons, offering a potential therapeutic target for enhancing tumour immunogenicity and overcoming immunotherapy resistance in PDAC. Data are available on reasonable request. All genomic sequencing data involved in this study have been deposited in the Gene Expression Omnibus database with the accession code GSE242098.

中文翻译：

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MED12 缺失激活内源性逆转录元件，使胰腺癌的免疫治疗敏感


目的 胰腺导管腺癌 （PDAC） 是最致命的癌症之一，其特点是致死性和有限的治疗选择，包括使用检查点阻断 （ICB） 免疫疗法。表观遗传失调是肿瘤发生的一个定义特征，与免疫监视有关，但在 PDAC 中仍然难以捉摸。设计 为了确定调节免疫监视的因素，我们在植入免疫功能正常或免疫缺陷小鼠的小鼠 PDAC 肿瘤模型中采用了体内表观遗传学聚焦的 CRISPR-Cas9 筛选。结果在这里，我们确定 MED12 是首发，成为 PDAC 中免疫肿瘤微环境 （TME） 的有效负调节剂。Med12 的缺失显着促进了肿瘤中免疫细胞的浸润和细胞毒性，包括 CD8+ T 细胞、自然杀伤 （NK） 和 NK1.1+ T 细胞，从而提高了 PDAC 小鼠模型中 ICB 治疗的敏感性。从机制上讲，MED12 稳定异染色质蛋白 HP1A 以抑制 H3K9me3 标记的内源性逆转录元件。MED12 丢失诱导的反转录转座子去抑制触发胞质核酸感应和随后的 I 型干扰素通路激活，最终导致强大的炎症 TME。此外，我们发现 MED12 表达与免疫反应通路、反转录转座子水平以及接受 ICB 治疗的 PDAC 患者的预后呈负相关。结论 总之，我们的研究结果强调了 MED12 通过反转录转座子的表观遗传沉默重塑免疫 TME 的关键作用，为增强肿瘤免疫原性和克服 PDAC 中的免疫治疗耐药性提供了潜在的治疗靶点。数据可应合理要求提供。 本研究涉及的所有基因组测序数据均已存入 Gene Expression Omnibus 数据库，登录码为 GSE242098。