Ralser Damian J, Herr Emmanuelle, de Vos Luka, Kulcsár Zsófi, Zarbl Romina, Klümper Niklas, Gielen Gerrit H, Maas Alexander Philippe, Hoffmann Friederike, Dietrich Jörn, Kuster Pia, Mustea Alexander, Glodde Nicole, Kristiansen Glen, Strieth Sebastian, Landsberg Jennifer, Dietrich Dimo
Department of Gynaecology and Gynaecological Oncology, University Medical Center Bonn (UKB), Bonn, Germany.
Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany.
Biomark Res. 2023 Jun 1;11(1):56. doi: 10.1186/s40364-023-00508-2.
Inducible T cell costimulator ICOS is an emerging target in immuno-oncology. The aim of this study was to investigate the epigenetic regulation of ICOS in melanoma by DNA methylation.
We comprehensively investigate ICOS DNA methylation of specific CpG sites and expression pattern within the melanoma microenvironment with regard to immune correlates, differentiation, clinical outcomes, and immune checkpoint blockade (ICB) response.
Our study revealed a sequence-contextual CpG methylation pattern consistent with an epigenetically regulated gene. We found a cell type-specific methylation pattern and locus-specific correlations and associations of CpG methylation with ICOS mRNA expression, immune infiltration, melanoma differentiation, prognosis, and response to ICB. High ICOS mRNA expression was identified as a surrogate for enriched immune cell infiltration and was associated with favorable overall survival (OS) in non-ICB-treated patients and predicted response and a prolonged progression-free survival (PFS) following ICB therapy initiation. ICOS hypomethylation, however, significantly correlated with poor OS in non-ICB patients but predicted higher response and prolonged PFS and OS in ICB-treated patients. Moreover, we observed cytoplasmic and sporadically nuclear tumor cell-intrinsic ICOS protein expression. Tumor cell-intrinsic ICOS protein and mRNA expression was inducible by pharmacological demethylation with decitabine.
Our study identified ICOS DNA methylation and mRNA expression as promising prognostic and predictive biomarkers for immunotherapy in melanoma and points towards a hitherto undescribed role of ICOS in tumor cells.
诱导性T细胞共刺激分子（ICOS）是免疫肿瘤学中一个新出现的靶点。本研究旨在通过DNA甲基化研究黑色素瘤中ICOS的表观遗传调控。
我们全面研究了黑色素瘤微环境中特定CpG位点的ICOS DNA甲基化及其与免疫相关性、分化、临床结局和免疫检查点阻断（ICB）反应相关的表达模式。
我们的研究揭示了一种与表观遗传调控基因一致的序列上下文CpG甲基化模式。我们发现了一种细胞类型特异性的甲基化模式，以及CpG甲基化与ICOS mRNA表达、免疫浸润、黑色素瘤分化、预后和ICB反应之间的位点特异性相关性和关联性。高ICOS mRNA表达被确定为免疫细胞浸润丰富的替代指标，与未接受ICB治疗患者的良好总生存期（OS）相关，并预测了ICB治疗开始后的反应和无进展生存期（PFS）延长。然而，ICOS低甲基化与未接受ICB治疗患者的不良OS显著相关，但在接受ICB治疗的患者中预测更高的反应以及更长的PFS和OS。此外，我们观察到细胞质和散在细胞核内的肿瘤细胞内源性ICOS蛋白表达。肿瘤细胞内源性ICOS蛋白和mRNA表达可通过地西他滨的药理学去甲基化诱导。
我们的研究确定ICOS DNA甲基化和mRNA表达是黑色素瘤免疫治疗有前景的预后和预测生物标志物，并指出ICOS在肿瘤细胞中迄今未被描述的作用。
