ELAVL1 通过调控 PD-L1 mRNA 的稳定性来破坏前列腺癌中 CD4阳性 T 细胞的浸润。

ELAVL1 regulates PD-L1 mRNA stability to disrupt the infiltration of CD4-positive T cells in prostate cancer.

机构信息

Department of Urology, Gongli Hospital of Shanghai Pudong New Area, Shanghai, China; Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

School of Nursing, Peking University, Beijing, China; Health Service Department of the Guard Bureau of the General Office of the Central Committee of the Communist Party of China, Beijing, China.

出版信息

Neoplasia. 2024 Nov;57:101049. doi: 10.1016/j.neo.2024.101049. Epub 2024 Sep 11.

DOI:10.1016/j.neo.2024.101049

PMID:39265220

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11416606/

Abstract

Prostate cancer (PCa) currently ranks second in male tumor mortality. Targeting immune checkpoint in tumor as immunotherapy is a new direction for tumor treatment. However, targeting PD-1/PD-L1 and CTLA4 to treat PCa has poor immunotherapeutic efficacy because PCa is known as a cold tumor. Understanding the mechanism of immunosuppression in PCa can promote the use of immunotherapy to treat PCa. ELAVL1 is highly expressed in many tumors, participates in almost all tumor biological activities and is an oncogene. ELAVL1 is also involved in the development and differentiation of T and B lymphocytes. However, the relationship between ELAVL1 and tumor immunity has not yet been reported. In recent years, ELAVL1 has been shown to regulate downstream targets in an m6A -dependent manner. PD-L1 has been shown to have m6A sites in multiple tumors that are regulated by m6A. In this study, ELAVL1 was highly expressed in PCa, and PCa with high ELAVL1 expression is immunosuppressive. Knocking down ELAVL1 reduced PD-L1 expression in PCa. Moreover, PD-L1 was shown to have an m6A site, and its m6A level was upregulated in PCa. ELAVL1 interacts with PD-L1 mRNA and promotes PD-L1 RNA stability via m6A, ultimately inhibiting the infiltration of CD4-positive T cells. In addition, androgen receptor (AR) was shown to be regulated with ELAVL1, and knocking down AR could also affect the expression of PD-L1. Therefore, ELAVL1 can directly or indirectly regulate the expression of PD-L1, thereby affecting the infiltration of CD4-positive T cells in PCa and ultimately leading to immune suppression.

摘要

前列腺癌（PCa）目前在男性肿瘤死亡率中排名第二。将肿瘤中的免疫检查点作为免疫疗法的靶点是肿瘤治疗的一个新方向。然而，靶向 PD-1/PD-L1 和 CTLA4 治疗 PCa 的免疫治疗效果不佳，因为 PCa 被认为是一种冷肿瘤。了解 PCa 中免疫抑制的机制可以促进免疫疗法治疗 PCa 的应用。ELAVL1 在许多肿瘤中高表达，参与几乎所有肿瘤的生物学活动，是一种癌基因。ELAVL1 还参与 T 和 B 淋巴细胞的发育和分化。然而，ELAVL1 与肿瘤免疫之间的关系尚未报道。近年来，ELAVL1 已被证明以 m6A 依赖的方式调节下游靶标。在多个肿瘤中，PD-L1 已被证明具有 m6A 位点，这些位点受 m6A 调节。在这项研究中，ELAVL1 在 PCa 中高表达，并且 ELAVL1 高表达的 PCa 具有免疫抑制性。敲低 ELAVL1 可降低 PCa 中 PD-L1 的表达。此外，PD-L1 被证明具有 m6A 位点，其 m6A 水平在 PCa 中上调。ELAVL1 与 PD-L1 mRNA 相互作用，并通过 m6A 促进 PD-L1 RNA 稳定性，最终抑制 CD4 阳性 T 细胞的浸润。此外，雄激素受体（AR）被证明受 ELAVL1 调节，敲低 AR 也会影响 PD-L1 的表达。因此，ELAVL1 可以直接或间接调节 PD-L1 的表达，从而影响 CD4 阳性 T 细胞在 PCa 中的浸润，最终导致免疫抑制。