ArticleLeukemia2021
Regulation of PD-L1 expression is a novel facet of cyclic-AMP-mediated immunosuppression.
Article in Leukemia, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 33 citations in OpenAlex.
- Integration of Multi-Omics Data To Understand the Multifaceted Role of RAMP1 across Different Cancer Types.Cell biochemistry and biophysics · 2026Review
- Extracellular vesicle-derived miRNA-182-5p educates macrophages towards an immunosuppressive phenotype in pancreatic cancer.Signal transduction and targeted therapy · 2026Article
- Artificial neural network-based immune biomarker signature predicts pathological complete response to neoadjuvant chemotherapy in HER2-negative breast cancer.Frontiers in oncology · 2026Article
- Real-world safety profile of roflumilast: a pharmacovigilance analysis using FDA adverse event reporting system and Canada vigilance database.Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques · 2025Article
- Microglial circDlg1 modulates neuroinflammation by blocking PDE4B ubiquitination-dependent degradation associated with Alzheimer's disease.Theranostics · 2025Article
- The multifaceted role of phosphodiesterase 4 in tumor: from tumorigenesis to immunotherapy.Frontiers in immunology · 2025Review
- Role of PD-1/PD-L1 signaling axis in oncogenesis and its targeting by bioactive natural compounds for cancer immunotherapy.Military Medical Research · 2024Review
- PDE4D drives rewiring of the MAPK pathway in BRAF-mutated melanoma resistant to MAPK inhibitors.Cell communication and signaling : CCS · 2024Article
- First-Line Combination of R-CHOP with the PDE4 Inhibitor Roflumilast for High-Risk DLBCL.Cancers · 2024Article
- Prognostic Protein Biomarker Screening for Thyroid Carcinoma Based on Cancer Proteomics Profiles.Biomedicines · 2024Article
- IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHCII complexes.Science advances · 2024Article
- IL-6-Driven Autocrine Lactate Promotes Immune Escape of Uveal Melanoma.Investigative ophthalmology & visual science · 2024Article
- cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment.Journal of hematology & oncology · 2024Review
- Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity.Nature communications · 2023Article
- The miR-199a-5p/PD-L1 axis regulates cell proliferation, migration and invasion in follicular thyroid carcinoma.BMC cancer · 2022Article
- CD73 Promotes Chronic Lymphocytic Leukemia.Cancers · 2022Article
- Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics.Nature reviews. Clinical oncology · 2022Review
- Article
- Cyclic adenosine monophosphate/phosphodiesterase 4 pathway associated with immune infiltration and PD-L1 expression in lung adenocarcinoma cells.Frontiers in oncology · 2022Article
- Editorial: Signaling pathways behind immune evasion and therapy resistance.Frontiers in immunology · 2022Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Cyclic-AMP (cAMP) exerts suppressive effects in the innate and adaptive immune system. The PD-1/PD-L1 immune checkpoint downregulates T-cell activity. Here, we examined if these two immunosuppressive nodes intersect. Using normal and malignant lymphocytes from humans, and the phosphodiesterase 4b (Pde4b) knockout mouse, we found that cAMP induces PD-L1 transcription and protein expression. Mechanistically, we discovered that the cAMP effectors PKA and CREB induce the transcription/secretion of IL-10, IL-8, and IL-6, which initiate an autocrine loop that activates the JAK/STAT pathway and ultimately increase PD-L1 expression in the cell surface. This signaling axis is disarmed at two specific nodes in subsets of diffuse large B-cell lymphoma, which may help explain the variable PD-L1 expression in these tumors. In vivo, we found that despite its immunosuppressive attributes, the PDE4 inhibitor roflumilast did not decrease the clinical activity of checkpoint inhibitors, an important clinical observation given the approved use of these agents in multiple diseases. In summary, we discovered that PD-L1 induction is a part of the repertoire of immunosuppressive actions mediated by cAMP, defined a cytokine-mediated autocrine loop that executes this action and, reassuringly, showed that PDE4 inhibition does not antagonize immune checkpoint blockade in an in vivo syngeneic lymphoma model.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.