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- Title
Trans-Regulation of Alternative PD-L1 mRNA Processing by CDK12 in Non-Small-Cell Lung Cancer Cells.
- Authors
Larsen, Trine V.; Maansson, Christoffer T.; Daugaard, Tina F.; Andresen, Brage S.; Sorensen, Boe S.; Nielsen, Anders L.
- Abstract
Immunotherapy using checkpoint inhibitors targeting the interaction between PD-1 on T cells and PD-L1 on cancer cells has shown significant results in non-small-cell lung cancer (NSCLC). Not all patients respond to the therapy, and PD-L1 expression heterogeneity is proposed to be one determinant for this. The alternative processing of PD-L1 RNA, which depends on an alternative poly-A site in intron 4, generates a shorter mRNA variant (PD-L1v4) encoding soluble PD-L1 (sPD-L1), relative to the canonical PD-L1v1 mRNA encoding membrane-associated PD-L1 (mPD-L1). This study aimed to identify factors influencing the ratio between these two PD-L1 mRNAs in NSCLC cells. First, we verified the existence of the alternative PD-L1 RNA processing in NSCLC cells, and from in silico analyses, we identified a candidate list of regulatory factors. Examining selected candidates showed that CRISPR/Cas9-generated loss-of-function mutations in CDK12 increased the PD-L1v4/PD-L1v1 mRNA ratio and, accordingly, the sPD-L1/mPD-L1 balance. The CDK12/13 inhibitor THZ531 could also increase the PD-L1v4/PD-L1v1 mRNA ratio and impact the PD-L1 transcriptional response to IFN-γ stimulation. The fact that CDK12 regulates PD-L1 transcript variant formation in NSCLC cells is consistent with CDK12's role in promoting transcriptional elongation over intron-located poly-A sites. This study lays the groundwork for clinical investigations to delineate the implications of the CDK12-mediated balancing of sPD-L1 relative to mPD-L1 for immunotherapeutic responses in NSCLC.
- Subjects
NON-small-cell lung carcinoma; CYCLIN-dependent kinases; PROGRAMMED death-ligand 1; CANCER cells; PROGRAMMED cell death 1 receptors; MESSENGER RNA
- Publication
Cells (2073-4409), 2023, Vol 12, Issue 24, p2844
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells12242844