eEF2 kinase enhances the expression of PD-L1

[Steve Hoimes]

#1376

eEF2 kinase enhances the expression of PD-L1 by promoting the translation of its mRNA

Abstract
Emerging advances in cancer therapy have transformed the landscape from conventional therapies towards cancer immunotherapy regimens. Recent discoveries have resulted in the development of clinical immune checkpoint inhibitors that are ‘game-changers’ for cancer immunotherapy. Here we show that eEF2K, an atypical protein kinase that inhibits the elongation stage of protein synthesis, actually promotes the synthesis of PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance. Ablation of eEF2K in prostate and lung cancer cells markedly reduced the expression levels of the PD-L1 protein. We show that eEF2K promotes the association of PD-L1 mRNAs with translationally active polyribosomes and that translation of the PD-L1 mRNA is regulated by a uORF (upstream open reading-frame) within its 5’-UTR (5’-untranslated region) which starts with a non-canonical CUG codon. This inhibitory effect is attenuated by eEF2K thereby allowing higher levels of translation of the PD-L1 coding region and enhanced expression of the PD-L1 protein. Moreover, eEF2K-depleted cancer cells are more vulnerable to immune attack by natural killer cells. Therefore, control of translation elongation can modulate the translation of this specific mRNA, one which contains an uORF that starts with CUG, and perhaps others that contain a similar feature. Taken together, our data reveal that eEF2K regulates PD-L1 expression at the level of the translation of its mRNA by virtue of a uORF in its 5’-region. This, and other roles of eEF2K in cancer cell biology (e.g., in cell survival and migration), may be exploited for the design of future therapeutic strategies.

Introduction
It is now clear that immunotherapy is a promising and effective approach to tackling a range of cancers (reviewed [1]). However, cancer cells can resist immune attack through so-called checkpoints, the two most-widely studied of which are programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte protein 4) [1]. PD-1, which is expressed on the surface of T lymphocytes, binds ligands expressed on other cells which, through PD-1, repress the activity of T cells. One such ligand is the protein PD-ligand 1 (PD-L1; [1], also termed CD274) which can be induced by signals such as interferon-γ (IFNγ), a cytokine. It is increasingly clear that countering these so-called immune check-points promotes immune responses, including against cancer cells. Indeed, antibodies that block either PD-1 or PD-L1 have shown striking efficacy in tackling a number of cancers (see, e.g., [1]).

As such, it is important to understand the mechanisms that control the expression of PD-L1 on cancer cells and thus enable them to ‘hide’ from immune surveillance. The expression of PD-L1 is known to be controlled at multiple levels including transcription of its gene, the stability of its mRNA and by microRNAs [1, 2].
read full paper – https://www.biorxiv.org/content/10.1101/2020.09.01.278655v1.full

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