RNA-binding proteins (RBPs) can recognize thousands of RNAs that help to maintain cell homeostasis, and RBP dysfunction is frequently observed in various cancers. However, whether specific RBPs are involved in tumor immune evasion by regulating programmed death ligand-1 (PD-L1) is unclear. Here, we perform targeted RBP CRISPR/Cas9 screening and identify density regulated re-initiation and release factor (DENR) as a PD-L1 regulator. DENR-depleted cancer cells exhibit reduced PD-L1 expression in vitro and in vivo. DENR depletion significantly suppresses tumor growth and enhances the tumor-killing activity of CD8 T cells. Mechanistically, DENR antagonizes the translational repression of three consecutive upstream open reading frames (uORFs) upstream of Janus kinase 2 (Jak2); thus, DENR deficiency impairs JAK2 translation and the IFNγ-JAK-STAT signaling pathway, resulting in reduced PD-L1 expression in tumors. Overall, we discover an RBP DENR that could regulate PD-L1 expression for tumor immune evasion, and highlight the potential of DENR as a therapeutic target for immunotherapy.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9018773PMC
http://dx.doi.org/10.1038/s41467-022-29754-yDOI Listing

Publication Analysis

Top Keywords

pd-l1 expression
16
tumor immune
12
immune evasion
12
jak2 translation
8
expression tumor
8
reduced pd-l1
8
denr
7
pd-l1
6
denr controls
4
controls jak2
4

Similar Publications

Copper Chelate Targeting Externalized Phosphatidylserine Inhibits PD-L1 Expression and Enhances Cancer Immunotherapy.

J Am Chem Soc

January 2025

Department of Pharmacy, The First Affiliated Hospital of USTC; Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Key Laboratory of Precision Pharmaceutical Preparation and Clinical Pharmacy, Hefei, Anhui 230026, China.

Inhibitors of the PD-1/PD-L1 immune checkpoint have revolutionized cancer treatment. However, the clinical response remains limited, with only 20% of patients benefiting from treatment and approximately 60% of PD-L1-positive patients exhibiting resistance. One key factor contributing to resistance is the externalization of phosphatidylserine (PS) on the surface of cancer cells, which suppresses immune responses and promotes PD-L1 expression, further hindering the efficacy of PD-L1 blockade therapies.

View Article and Find Full Text PDF

Background/objectives: Pembrolizumab monotherapy is approved in Canada for first-line treatment of advanced NSCLC with PD-L1 ≥ 50% and no EGFR/ALK aberrations. However, approximately 55% of these patients do not respond to pembrolizumab, underscoring the need for the early intervention of non-responders to optimize treatment strategies. Distinguishing the 55% sub-cohort prior to treatment is a real-world dilemma.

View Article and Find Full Text PDF

The Role of YY1 in the Regulation of LAG-3 Expression in CD8 T Cells and Immune Evasion in Cancer: Therapeutic Implications.

Cancers (Basel)

December 2024

Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA.

The treatment of cancers with immunotherapies has yielded significant milestones in recent years. Amongst these immunotherapeutic strategies, the FDA has approved several checkpoint inhibitors (CPIs), primarily Anti-Programmed Death-1 (PD-1) and Programmed Death Ligand-1/2 (PDL-1/2) monoclonal antibodies, in the treatment of various cancers unresponsive to immune therapeutics. Such treatments resulted in significant clinical responses and the prolongation of survival in a subset of patients.

View Article and Find Full Text PDF

CD8+ and CD8- NK Cells and Immune Checkpoint Networks in Peripheral Blood During Healthy Pregnancy.

Int J Mol Sci

January 2025

Department of Medical Microbiology and Immunology, Medical School, University of Pecs, 12 Szigeti Street, 7624 Pecs, Hungary.

Pregnancy involves significant immunological changes to support fetal development while protecting the mother from infections. A growing body of evidence supports the importance of immune checkpoint pathways, especially at the maternal-fetal interface, although limited information is available about the peripheral expression of these molecules by CD8+ and CD8- NK cell subsets during the trimesters of pregnancy. Understanding the dynamics of these immune cells and their checkpoint pathways is crucial for elucidating their roles in pregnancy maintenance and potential complications.

View Article and Find Full Text PDF

The expression of BHLHE22 in endometrial carcinoma: Associations with mismatch repair protein expression status, tumor-infiltrating immune cells, programmed death-ligand 1 and clinical outcomes.

Taiwan J Obstet Gynecol

January 2025

Department of Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan; Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. Electronic address:

Objective: Endometrial cancer (EC) shows substantial heterogeneity in their immune microenvironment. BHLHE22 is consistently hypermethylated in EC and high expression of BHLHE22 is likely to be immunosuppressive in the tumor microenvironment. Herein, we evaluated expression of BHLHE22, programmed cell death ligand-1 (PD-L1), CD8, CD68 and mismatch repair proteins in EC.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!