University of Siena, Siena, Italy.
BIOGEM Institute of Molecular Biology and Genetics, Ariano Irpino, Italy.
J Transl Med. 2024 Mar 1;22(1):223. doi: 10.1186/s12967-024-05040-x.
Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor, that is refractory to standard treatment and to immunotherapy with immune-checkpoint inhibitors (ICI). Noteworthy, melanoma brain metastases (MM-BM), that share the same niche as GBM, frequently respond to current ICI therapies. Epigenetic modifications regulate GBM cellular proliferation, invasion, and prognosis and may negatively regulate the cross-talk between malignant cells and immune cells in the tumor milieu, likely contributing to limit the efficacy of ICI therapy of GBM. Thus, manipulating the tumor epigenome can be considered a therapeutic opportunity in GBM.
Microarray transcriptional and methylation profiles, followed by gene set enrichment and IPA analyses, were performed to study the differences in the constitutive expression profiles of GBM vs MM-BM cells, compared to the extracranial MM cells and to investigate the modulatory effects of the DNA hypomethylating agent (DHA) guadecitabine among the different tumor cells. The prognostic relevance of DHA-modulated genes was tested by Cox analysis in a TCGA GBM patients' cohort.
The most striking differences between GBM and MM-BM cells were found to be the enrichment of biological processes associated with tumor growth, invasion, and extravasation with the inhibition of MHC class II antigen processing/presentation in GBM cells. Treatment with guadecitabine reduced these biological differences, shaping GBM cells towards a more immunogenic phenotype. Indeed, in GBM cells, promoter hypomethylation by guadecitabine led to the up-regulation of genes mainly associated with activation, proliferation, and migration of T and B cells and with MHC class II antigen processing/presentation. Among DHA-modulated genes in GBM, 7.6% showed a significant prognostic relevance. Moreover, a large set of immune-related upstream-regulators (URs) were commonly modulated by DHA in GBM, MM-BM, and MM cells: DHA-activated URs enriched for biological processes mainly involved in the regulation of cytokines and chemokines production, inflammatory response, and in Type I/II/III IFN-mediated signaling; conversely, DHA-inhibited URs were involved in metabolic and proliferative pathways.
Epigenetic remodeling by guadecitabine represents a promising strategy to increase the efficacy of cancer immunotherapy of GBM, supporting the rationale to develop new epigenetic-based immunotherapeutic approaches for the treatment of this still highly deadly disease.
多形性胶质母细胞瘤（GBM）是一种高度侵袭性的原发性脑肿瘤，对标准治疗和免疫检查点抑制剂（ICI）免疫疗法均具有抗性。值得注意的是，黑色素瘤脑转移瘤（MM-BM）与 GBM 具有相同的生态位，经常对当前的 ICI 治疗产生反应。表观遗传修饰调控 GBM 细胞的增殖、侵袭和预后，并可能负调控肿瘤微环境中恶性细胞与免疫细胞之间的串扰，这可能限制了 GBM 的 ICI 治疗效果。因此，操纵肿瘤表观基因组可以被认为是 GBM 的一种治疗机会。
进行了微阵列转录组和甲基化谱分析，随后进行了基因集富集和 IPA 分析，以研究 GBM 与 MM-BM 细胞与颅外 MM 细胞的组成型表达谱之间的差异，并研究 DNA 低甲基化剂（DHA）地西他滨在不同肿瘤细胞中的调节作用。在 TCGA GBM 患者队列中，通过 Cox 分析测试了 DHA 调节基因的预后相关性。
GBM 与 MM-BM 细胞之间最显著的差异是与肿瘤生长、侵袭和外渗相关的生物学过程的富集，而在 GBM 细胞中 MHC II 抗原加工/呈递被抑制。地西他滨的治疗减少了这些生物学差异，使 GBM 细胞向更具免疫原性的表型发展。事实上，在地西他滨处理的 GBM 细胞中，启动子低甲基化导致主要与 T 和 B 细胞的激活、增殖和迁移以及 MHC II 抗原加工/呈递相关的基因上调。在地西他滨调节的 GBM 基因中，有 7.6%显示出显著的预后相关性。此外，在地西他滨调节的 GBM、MM-BM 和 MM 细胞中，一组常见的免疫相关上游调节剂（URs）也被共同调节：地西他滨激活的 URs 富集的生物学过程主要涉及细胞因子和趋化因子产生、炎症反应以及 I 型/II 型/III 型 IFN 介导的信号转导的调节；相反，地西他滨抑制的 URs 参与代谢和增殖途径。
地西他滨的表观遗传重塑代表了提高 GBM 癌症免疫治疗效果的有前途的策略，为开发新的基于表观遗传的免疫治疗方法治疗这种仍然具有高致死性的疾病提供了依据。
