Diacylglycerol kinases in cancer.

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.

Diacylglycerol kinase ζ limits the polarized recruitment of diacylglycerol-enriched organelles to the immune synapse in T cells.

The antigen-induced formation of an immune synapse (IS) between T cells and antigen-presenting cells results in the rapid generation of the lipid second messenger diacylglycerol (DAG) in T cells. Diacylglycerol kinase ζ (DGKζ) converts DAG into phosphatidic acid (PA). Cytotoxic T lymphocytes (CTLs) from mice deficient in DGKζ have enhanced antiviral and antitumor activities, indicating that the amount of DAG controls the effectiveness of the T cell response. We characterized the second C1 domain of protein kinase Cθ (PKCθ), a DAG-binding protein that is specifically recruited to the IS, as a biological sensor to observe the generation of a DAG gradient during IS formation. In experiments with transgenic mouse CTLs expressing the OT-I T cell receptor (TCR), we showed that both strong and weak interactions between antigen and the TCR led to the rapid generation of DAG, whereas only strong interactions induced the movement of DAG-enriched organelles toward the IS. In DGKζ-deficient CTLs, antigen stimulation led to the enhanced accumulation of DAG-containing organelles at the IS; however, impaired activation of the PA effector PKCζ resulted in lack of reorientation of the microtubule-organizing center toward the IS, a process needed for effective T cell activation. Together, these data suggest that the activation of DGKζ downstream of antigen recognition provides a mechanism that ensures the activation of PA-dependent signaling as a direct result of the strength of TCR-dependent DAG mobilization.