ELAVL1 regulates PD-L1 mRNA stability to disrupt the infiltration of CD4-positive T cells in prostate cancer
Zhonglin Cai1, Xiuxia Zhai2, Jidong Xu3
1Department 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.
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.
Insights
High ELAVL1 expression in prostate cancer (PCa) promotes tumor immunosuppression by stabilizing PD-L1 RNA via m6A modification, inhibiting CD4-positive T cell infiltration. This sheds light on PCa
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Prostate cancer (PCa) is a leading cause of male cancer mortality.
- PCa is considered a 'cold tumor,' exhibiting poor response to current immunotherapies like PD-1/PD-L1 and CTLA-4 blockade.
- Understanding PCa's immunosuppressive mechanisms is crucial for developing effective immunotherapies.
Purpose of the Study:
- To investigate the role of ELAVL1 in prostate cancer immunity.
- To elucidate the molecular mechanisms by which ELAVL1 influences PD-L1 expression and T cell infiltration in PCa.
- To explore the relationship between ELAVL1, m6A modification, and androgen receptor (AR) signaling in PCa.
Main Methods:
- Analysis of ELAVL1 expression in PCa tissues.
- Knockdown experiments to assess the impact of ELAVL1 on PD-L1 expression and T cell infiltration.
- Investigation of m6A modification sites on PD-L1 mRNA.
- Assessment of ELAVL1 interaction with PD-L1 mRNA.
- Exploration of the interplay between ELAVL1 and androgen receptor (AR) in PCa.
Main Results:
- ELAVL1 is highly expressed in PCa and associated with an immunosuppressive tumor microenvironment.
- Knocking down ELAVL1 reduces PD-L1 expression in PCa.
- PD-L1 exhibits m6A modification, with upregulated levels in PCa.
- ELAVL1 interacts with PD-L1 mRNA, enhancing its stability through m6A modification, which inhibits CD4-positive T cell infiltration.
- ELAVL1 regulates AR, and AR knockdown affects PD-L1 expression.
Conclusions:
- ELAVL1 promotes prostate cancer immunosuppression by directly or indirectly regulating PD-L1 expression via m6A-dependent RNA stabilization.
- This regulation leads to decreased CD4-positive T cell infiltration in PCa.
- Targeting ELAVL1 may represent a novel therapeutic strategy to enhance immunotherapy efficacy in prostate cancer.
