title: Diacylglycerol kinases in cancer.
abstract: Diacylglycerol kinases (DGK) are a family of enzymes that catalyze the transformation of diacylglycerol into phosphatidic acid. In T lymphocytes, DGKα and ζ limit the activation of the PLCγ/Ras/ERK axis, providing a critical checkpoint to inhibit T cell responses. Upregulation of these isoforms limits Ras activation, leading to hypo-responsive, anergic states similar to those caused by tumors. Recent studies have identified DGKα upregulation in tumor lymphocyte infiltrates, and cells from DGKα and ζ deficient mice show enhanced antitumor activity, suggesting that limitation of DAG based signals by DGK is used by tumors to evade immune attack. DGKα expression is low or even absent in other healthy cells like melanocytes, hepatocytes or neurons. Expression of this isoform, nevertheless is upregulated in melanoma, hepatocarcinoma and glioblastoma where DGKα contributes to the acquisition of tumor metastatic traits. A model thus emerges where tumor milieu fosters DGKα expression in tumors as well as in tumor infiltrating lymphocytes with opposite consequences. Here we review the mechanisms and targets that facilitate tumor "addiction" to DGKα, and discuss its relevance in the more advanced forms of cancer for tumor immune evasion. A better knowledge of this function offers a new perspective in the search of novel approaches to prevent inhibition of immune attack in cancer. Part of the failure in clinical progress may be attributed to the complexity of the tumor/T lymphocyte interaction. As they develop, tumors use a number of mechanisms to drive endogenous, tumor reactive T cells to a general state of hyporesponsiveness or anergy. A better knowledge of the molecular mechanisms that tumors use to trigger T cell anergic states will greatly help in the advance of immunotherapy research.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), E-28049, Madrid, Spain. Electronic address: imerida@cnb.csic.es.
authors.forename: Isabel
authors.initials: I
authors.lastname: Mérida
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), E-28049, Madrid, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Torres-Ayuso
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), E-28049, Madrid, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Ávila-Flores
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), E-28049, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Arranz-Nicolás
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), E-28049, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Andrada
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), E-28049, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Tello-Lafoz
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), E-28049, Madrid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Liébana
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), E-28049, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Arcos
mesh_terms: D000818:Animals; D017635:Clonal Anergy; D019852:Diacylglycerol Kinase / Q000235:genetics* / Q000276:immunology; D004075:Diglycerides / Q000276:immunology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D010712:Phosphatidic Acids / Q000276:immunology / Q000378:metabolism; D051966:Phospholipase C gamma / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019139:Tumor Escape / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics / Q000276:immunology
chemical_list: C011439:1,2-diacylglycerol; D004075:Diglycerides; D010712:Phosphatidic Acids; C526463:DGKZ protein, human; D019852:Diacylglycerol Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D051966:Phospholipase C gamma; D018631:ras Proteins