ArticleCancer immunology, immunotherapy : CII2021
Diacylglycerol kinase α inhibition cooperates with PD-1-targeted therapies to restore the T cell activation program.
Article in Cancer immunology, immunotherapy : CII, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 25 citations in OpenAlex.
- Hyperprogression of cutaneous T cell lymphoma after anti-PD-1 treatment.JCI insight · 2023Trial
- A dual diacylglycerol kinase (DGK) alpha/zeta inhibitor augments the activity of human tumor infiltrating lymphocytes inOncoimmunology · 2026Article
- Article
- DGKs in lipid signaling and disease intervention: structural basis, pathological mechanisms, and emerging therapeutic strategies.Cellular & molecular biology letters · 2025Review
- Epigenetic regulators combined with tumour immunotherapy: current status and perspectives.Clinical epigenetics · 2025Review
- Diacylglycerol Kinases and Its Role in Lipid Metabolism and Related Diseases.International journal of molecular sciences · 2024Review
- Strategies to overcome tumor microenvironment immunosuppressive effect on the functioning of CAR-T cells in high-grade glioma.Therapeutic advances in medical oncology · 2024Review
- Wiskott-Aldrich syndrome protein interacts and inhibits diacylglycerol kinase alpha promoting IL-2 induction.Frontiers in immunology · 2023Article
- The expanding role for small molecules in immuno-oncology.Nature reviews. Drug discovery · 2022Review
- Overarching roles of diacylglycerol signaling in cancer development and antitumor immunity.Science signaling · 2022Review
- Combination therapy for hepatocellular carcinoma with diacylglycerol kinase alpha inhibition and anti-programmed cell death-1 ligand blockade.Cancer immunology, immunotherapy : CII · 2022Article
- Immune Checkpoint Receptors Signaling in T Cells.International journal of molecular sciences · 2022Review
- Review
- Review
- Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1.International journal of molecular sciences · 2021Review
- PD-1/PD-L1 Checkpoint Inhibitors in Tumor Immunotherapy.Frontiers in pharmacology · 2021Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundAntibody-based therapies blocking the programmed cell death-1/ligand-1 (PD-1/PD-L1) axis have provided unprecedent clinical success in cancer treatment. Acquired resistance, however, frequently occurs, commonly associated with the upregulation of additional inhibitory molecules. Diacylglycerol kinase (DGK) α limits the extent of Ras activation in response to antigen recognition, and its upregulation facilitates hypofunctional, exhausted T cell states. Pharmacological DGKα targeting restores cytotoxic function of chimeric antigen receptor and CD8 MATERIALS AND
methodsWe used a human triple parameter reporter cell line to investigate DGKα contribution to the PD-1/PD-L1 inhibitory pathway. We also addressed the impact of deleting DGKα expression in the growth dynamics and systemic tumor-derived effects of a PD-1-related tumor model, the MC38 colon adenocarcinoma.
resultsWe identify DGKα as a contributor to the PD-1/PD-L1 axis that strongly limits the Ras/ERK/AP-1 pathway. DGKα function reinforces exhausted T cell phenotypes ultimately promoting tumor growth and generalized immunosuppression. Pharmacological DGKα inhibition selectively enhances AP-1 transcription and, importantly, cooperates with antibodies blocking the PD-1/PD-L1 interrelation.
conclusionsOur results indicate that DGKα inhibition could provide an important mechanism to revert exhausted T lymphocyte phenotypes and thus favor proper anti-tumor T cell responses. The cooperative effect observed after PD-1/PD-L1 and DGKα blockade offers a promising strategy to improve the efficacy of immunotherapy in the treatment of cancer.
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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.