前列腺癌免疫抑制中肿瘤免疫动态的表观遗传学基础。

Epigenetic underpinnings of tumor-immune dynamics in prostate cancer immune suppression.

机构信息

Division of Urologic Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA.

Division of Urologic Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA; Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA.

出版信息

Trends Cancer. 2024 Apr;10(4):369-381. doi: 10.1016/j.trecan.2024.01.004. Epub 2024 Feb 9.

DOI:10.1016/j.trecan.2024.01.004

PMID:38341319

Abstract

Prostate cancer (PC) is immunosuppressive and refractory to immunotherapy. Infiltration of myeloid-derived suppressor cells (MDSCs) and senescent-like neutrophils and T cell exhaustion are observed in the tumor microenvironment (TME) following androgen receptor (AR) antagonism with antiandrogens or androgen ablation. De novo post-translational acetylation of the AR, HOXB13, and H2A at K609, K13, and K130, respectively, and phosphorylation of H4 at Y88 have emerged as key epigenetic modifications associated with castration-resistant PC (CRPC). The resulting chromatin changes are integrated into cellular processes via phosphorylation of the AR, ACK1, ATPF1A, and SREBP1 at Y267, Y284, Y243/Y246, and Y673/Y951, respectively. In this review, we discuss how these de novo epigenetic alterations drive resistance and how efforts aimed at targeting these regulators may overcome immune suppression observed in PC.

摘要

前列腺癌（PC）具有免疫抑制性，且对免疫疗法有抗性。在雄激素受体（AR）拮抗剂（如抗雄激素或去势治疗）拮抗 AR 后，在肿瘤微环境（TME）中观察到髓系来源的抑制细胞（MDSCs）和衰老样中性粒细胞的浸润，以及 T 细胞耗竭。AR、HOXB13 和 H2A 在 K609、K13 和 K130 处的从头翻译后乙酰化，以及 H4 在 Y88 处的磷酸化，已成为与去势抵抗性 PC（CRPC）相关的关键表观遗传修饰。这些染色质变化通过 AR、ACK1、ATPF1A 和 SREBP1 在 Y267、Y284、Y243/Y246 和 Y673/Y951 处的磷酸化，整合到细胞过程中。在这篇综述中，我们讨论了这些新出现的表观遗传改变如何驱动耐药性，以及靶向这些调节剂的努力如何克服 PC 中观察到的免疫抑制。