State Key Laboratory of Systems Medicine for Cancer, Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Centre of Biomedical Systems and Informatics, ZJU-UoE Institute, Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining, Zhejiang, China.
Gut. 2024 Nov 11;73(12):1999-2011. doi: 10.1136/gutjnl-2024-332350.
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.
To identify the factors that modulate immune surveillance, we employed epigenetic-focused CRISPR-Cas9 screen in mouse PDAC tumour models engrafted in either immunocompetent or immunodeficient mice.
Here, we identified MED12 as a top hit, emerging as a potent negative modulator of immune tumour microenviroment (TME) in PDAC. Loss of 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 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.
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.
胰腺导管腺癌（PDAC）是最致命的癌症之一，其致命性和有限的治疗选择使其成为一个挑战，包括利用检查点阻断（ICB）免疫疗法。表观遗传失调是肿瘤发生的一个决定性特征，它与免疫监视有关，但在 PDAC 中仍然难以捉摸。
为了确定调节免疫监视的因素，我们在免疫功能正常或免疫缺陷的小鼠中植入的小鼠 PDAC 肿瘤模型中使用了针对表观遗传的 CRISPR-Cas9 筛选。
在这里，我们确定 MED12 是一个重要的靶点，它是 PDAC 中免疫肿瘤微环境（TME）的有效负调节剂。缺失显著促进了包括 CD8 T 细胞、自然杀伤（NK）和 NK1.1 T 细胞在内的免疫细胞在肿瘤中的浸润和细胞毒性，从而提高了 PDAC 小鼠模型中 ICB 治疗的敏感性。从机制上讲，MED12 稳定了异染色质蛋白 HP1A，以抑制 H3K9me3 标记的内源性反转录元件。缺失导致反转录元件的去抑制引发细胞质核酸感应，并随后激活 I 型干扰素途径，最终导致强烈的炎症性 TME。此外，我们发现 MED12 表达与免疫反应途径、反转录元件水平以及接受 ICB 治疗的 PDAC 患者的预后呈负相关。
总之，我们的研究结果强调了 MED12 通过表观遗传沉默反转录元件重塑免疫 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一个潜在的治疗靶点。
