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

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.