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. 2017 Mar 3:5:16.
doi: 10.3389/fcell.2017.00016. eCollection 2017.

DGK-α: A Checkpoint in Cancer-Mediated Immuno-Inhibition and Target for Immunotherapy

Elfriede Noessner  1
Affiliations

DGK-α: A Checkpoint in Cancer-Mediated Immuno-Inhibition and Target for Immunotherapy

Elfriede Noessner. Front Cell Dev Biol. .

Abstract

Immunotherapy is moving to the forefront of cancer treatments owing to impressive durable responses achieved with checkpoint blockade antibodies and adoptive T-cell therapy. Still, improvements are necessary since, overall, only a small percentage of patients benefit from current therapies. Here, I summarize evidence that DGK-α may represent an immunological checkpoint suppressing the activity of cytotoxic immunocytes in the tumor microenvironment. DGK-inhibitors can restore the antitumor function of tumor-suppressed adaptive and innate cytotoxic immunocytes. The activity of DGK-inhibitors lays downstream of current checkpoint blockade antibodies. Thus, synergistic effects are expected from combination strategies. Moreover, DGK-inhibitors may permit a double-strike attack on tumor cells as DGK-inhibition may not only re-instate immunological tumor attack but also may harm tumor cells directly by interfering with oncogenic survival pathways. Together, DGK-inhibitors have very promising characteristics and may be beneficially included into the armamentarium of cancer immunotherapeutics.

Keywords: anergy; diacylglycerol kinase; human tumor; immunotherapy; renal cell carcinoma; tumor-infiltrating lymphocytes.

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Figures

Figure 1
Figure 1
Processes to activate T cell immunity against cancer: In the lymph node, T cell priming occurs through mature dendritic cells (DCs) presenting tumor-derived antigens. The number of arising T helper (TH) cells and cytotoxic T cells (CTL) is limited through cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Antibodies against CTLA-4 allow for activation of more T cells due to the amelioration of negative signals during T-cell priming. In addition, anti-CTLA-4 inhibits Treg which express high levels of CTLA-4 constitutively. Activated T cells migrate into the tumor milieu where they engage with tumor cells expressing peptide-MHC that can be recognized by the T cell receptor (TCR). TCR-pMHC interaction will activate tumor cell killing processes unless suppression occurs through concomitant PD-1/PD-L1 interaction. Killing of tumor cells can occur if the negative signaling is blocked through anti-PD-1 or anti-PD-L1 antibodies. NK cells can recognize tumor cells that express low or no MHC and, thus, cooperate with CTL to prevent tumor escape. If tumor cell killing occurs, antigen is released which can be taken up by immature DCs. Immature DCs can mature to mature DCs which then present antigen to T cells in the lymph node, leading to the generation of new tumor-reactive T cells. If the natural process of antigen presentation does not occur (efficiently), therapeutic vaccination using ex vivo generated antigen-loaded DCs or peptides may be applied.
Figure 2
Figure 2
Theoretical concept of combined application of checkpoint blockade therapy and DGK-inhibition. (A) Functional unresponsiveness of TILs in the tumor milieu may have different mutually non-exclusive causes: (i) Ligation of PD-1 on T cells by tumor expressed PD-L1 may cause recruitment of phosphatase SHP2 and subsequent dephosphorylation of the TCR proximal signal transmitter Lck as well as attenuation of AKT-signaling. Consequently, signals initiated by TCR-peptide/MHC recognition intended to activate T-cell effector function (degranulation leading to lysis of target cells as well as IFNγ) are interrupted. The signal interruption through PD-1/PD-L1 classically occurs as a consequence of T-cell exhaustion. (ii) Anergy is another mechanism of T-cell silencing. The underlying cause is upregulated diacylglycerol kinase (DGK), in T cells mainly DGK-α and DGK-ζ. DGKs metabolize diacylglycerol (DAG) to phosphatidic acid (PA) lowering DAG levels which are necessary to activate TCR distal signaling through Ras/ERK. The ERK pathway is critically import for the degranulation process that delivers lytic proteins into the target cell for target cell death. (B) De-blocking the exhaustion pathway through checkpoint antibodies (anti-PD-1/PD-L1) releases the proximal brake at the TCR-associated molecules (Lck- and AKT-phosphorylation); however, distal brakes through DGK may still be active (blocked ERK pathway and attenuated PKC- and NFκB-activation) preventing full activation of the T cell‘s antitumor functions (degranulation, IFNγ). (C) Combined treatment with checkpoint antibodies and DGK-inhibitor may be required to open the signaling cascade fully, allowing effector function.
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References

    1. Arumugam V., Bluemn T., Wesley E., Schmidt A. M., Kambayashi T., Malarkannan S., et al. . (2015). TCR signaling intensity controls CD8+ T cell responsiveness to TGF-ß. J. Leukoc. Biol. 98, 703–712. 10.1189/jlb.2HIMA1214-578R - DOI - PMC - PubMed
    1. Beyer M., Karbach J., Mallmann M. R., Zander T., Eggle D., Classen S., et al. . (2009). Cancer vaccine enhanced, non-tumor-reactive CD8+ T cells exhibit a distinct molecular program associated with “division arrest anergy”. Cancer. Res. 69, 4346–4354. 10.1158/0008-5472.CAN-08-3796 - DOI - PubMed
    1. Callahan M. K., Postow M. A., Wolchok J. D. (2016). Targeting T Cell Co-receptors for Cancer Therapy. Immunity 44, 1069–1078. 10.1016/j.immuni.2016.04.023 - DOI - PubMed
    1. Chen S. S., Hu Z., Zhong X. P. (2016). Diacylglycerol kinases in T cell tolerance and effector function. Front. Cell Dev. Biol. 4:130. 10.3389/fcell.2016.00130 - DOI - PMC - PubMed
    1. Dominguez C. L., Floyd D. H., Xiao A., Mullins G. R., Kefas B. A., Xin W., et al. . (2013). Diacylglycerol kinase α is a critical signaling node and novel therapeutic target in glioblastoma and other cancers. Cancer Discov. 3, 782–797. 10.1158/2159-8290.CD-12-0215 - DOI - PMC - PubMed