RelB upregulates PD-L1 and exacerbates prostate cancer immune evasion.

The interaction between programmed death receptor (PD-1) and its ligand (PD-L1) is essential for suppressing activated T-lymphocytes. However, the precise mechanisms underlying PD-L1 overexpression in tumours have yet to be fully elucidated. Here, we describe that RelB participates in the immune evasion of prostate cancer (PCa) via cis/trans transcriptional upregulation of PD-L1. Based on transcriptome results, RelB was manipulated in multiple human and murine PCa cell lines. Activated CD4+ and CD8+ T cells were cocultured with PCa cells with different levels of RelB to examine the effect of tumourous RelB on T cell immunity. Male mice were injected with murine PCa cells to validate the effect of RelB on the PD-1/PD-L1-mediated immune checkpoint using both tumour growth and metastatic experimental models. PD-L1 is uniquely expressed at a high level in PCa with high constitutive RelB and correlates with the patients' Gleason scores. Indeed, a high level of PD-L1 is associated with RelB nuclear translocation in AR-negative aggressive PCa cells. Conversely, the silencing of RelB in advanced PCa cells resulted in reduced PD-L1 expression and enhanced susceptibility of PCa cells to the T cell immune response in vitro and in vivo. Mechanistically, a proximal NF-κB enhancer element was identified in the core promoter region of the human CD274 gene, which is responsible for RelB-mediated PD-L1 transcriptional activation. This finding provides an informative insight into immune checkpoint blockade by administering RelB within the tumour microenvironment. This study deciphers the molecular mechanism by which tumourous RelB contributes to immune evasion by inhibiting T cell immunity via the amplification of the PD-L1/PD-1-mediated immune checkpoint. © 2022. The Author(s).

Citation

Yanyan Zhang, Shuyi Zhu, Yuanyuan Du, Fan Xu, Wenbo Sun, Zhi Xu, Xiumei Wang, Peipei Qian, Qin Zhang, Jifeng Feng, Yong Xu. RelB upregulates PD-L1 and exacerbates prostate cancer immune evasion. Journal of experimental & clinical cancer research : CR. 2022 Feb 17;41(1):66

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PMID: 35177112

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