BACKGROUND Upregulation of the histone methyltransferase enzyme EZH2 and its histone modification H3K27me3 has been linked to melanoma progression, metastasis, and resistance to immune checkpoint blockade (ICB). In clinical trials, EZH2 inhibitors are currently tested to overcome resistance to ICB. The aim of this study is to evaluate expression patterns and the predictive value of H3K27me3 and EZH2 in metastatic melanoma samples prior to ICB. As H3K27me3 expression has been associated with a dedifferentiated, invasive melanoma phenotype, we also investigated the prognostic value of H3K27me3 expression in primary melanomas. RESULTS H3K27me3 and EZH2 expression were evaluated in a cohort of 44 metastatic melanoma samples before ICB using immunohistochemistry (IHC). 29/44 (66%) of melanomas showed H3K27me3 expression, and 6/44 (14%) showed EZH2 expression. No predictive value for therapeutic response to anti-PD-1 therapy could be found for H3K27me3 or EZH2 expression on melanoma cells. To investigate the prognostic significance of H3K27me3, we analyzed H3K27me3 expression in a representative cohort of 136 primary melanomas with known sentinel lymph node status. H3K27me3 expression is associated with increased tumor thickness and nodal involvement. Melanoma metastases showed a higher expression of H3K27me3 in comparison to primary melanomas. In human melanoma cell lines, TNFα and INFγ could not induce H3K27me3 expression. CONCLUSION Our study shows that H3K27me3 expression is more frequent than EZH2 and is associated with a more invasive and metastatic melanoma cell phenotype. We suggest that H3K27me3 expression by IHC might be a suitable method to evaluate the activity of EZH2 inhibitors in clinical trials.

中文翻译：

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H3K27me3和EZH2在黑色素瘤中的表达：黑色素瘤进展和对免疫检查点封锁反应的相关性。

背景技术组蛋白甲基转移酶EZH2及其组蛋白修饰H3K27me3的上调与黑色素瘤的进展，转移和对免疫检查点阻断（ICB）的抵抗力有关。在临床试验中，目前已测试了EZH2抑制剂以克服对ICB的耐药性。这项研究的目的是评估ICB之前转移性黑色素瘤样本中H3K27me3和EZH2的表达模式和预测价值。由于H3K27me3表达与去分化的浸润性黑色素瘤表型有关，因此我们还研究了H3K27me3表达在原发性黑色素瘤中的预后价值。结果在ICB之前使用免疫组织化学（IHC）技术对44例转移性黑色素瘤样本中的H3K27me3和EZH2表达进行了评估。29/44（66％）黑色素瘤显示H3K27me3表达，6/44（14％）显示EZH2表达。对于黑色素瘤细胞上的H3K27me3或EZH2表达，未发现针对抗PD-1治疗的治疗反应的预测价值。为了调查H3K27me3的预后意义，我们分析了H3K27me3在136个具有已知前哨淋巴结状态的原发性黑色素瘤的代表性队列中的表达。H3K27me3表达与肿瘤厚度增加和淋巴结转移有关。与原发性黑色素瘤相比，黑色素瘤转移灶显示H3K27me3的表达更高。在人黑素瘤细胞系中，TNFα和INFγ不能诱导H3K27me3表达。结论我们的研究表明H3K27me3表达比EZH2更频繁，并且与更具侵袭性和转移性的黑色素瘤细胞表型相关。