TY - JOUR
T1 - Diacylglycerol kinases in cancer
AU - Mérida, Isabel
AU - Torres-Ayuso, Pedro
AU - Ávila-Flores, Antonia
AU - Arranz-Nicolás, Javier
AU - Andrada, Elena
AU - Tello-Lafoz, María
AU - Liébana, Rosa
AU - Arcos, Raquel
N1 - Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - Animals
KW - Clonal Anergy
KW - Diacylglycerol Kinase/genetics
KW - Diglycerides/immunology
KW - Extracellular Signal-Regulated MAP Kinases/genetics
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Mice
KW - Neoplasms/genetics
KW - Phosphatidic Acids/immunology
KW - Phospholipase C gamma/genetics
KW - Signal Transduction
KW - T-Lymphocytes/immunology
KW - Tumor Escape/genetics
KW - ras Proteins/genetics
UR - http://www.scopus.com/inward/record.url?scp=85008700489&partnerID=8YFLogxK
UR - http://europepmc.org/abstract/med/27697466
U2 - 10.1016/j.jbior.2016.09.005
DO - 10.1016/j.jbior.2016.09.005
M3 - Review article
C2 - 27697466
SN - 2212-4926
VL - 63
SP - 22
EP - 31
JO - Advances in Biological Regulation
JF - Advances in Biological Regulation
ER -