Diacylglycerol Kinases (DGKs): Novel Targets for Improving T Cell Activity in Cancer

Riese, Matthew J.; Moon, Edmund K.; Johnson, Bryon D.; Albelda, Steven Μ.

doi:10.3389/fcell.2016.00108

Cited by 50 publications

(41 citation statements)

References 63 publications

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“…In particular, our screen showed that knockdown of diacylglycerol kinase (DGK) family of genes resulted in increased sensitivity to CAR-T cells. Previous groups have shown that inhibition of DGK-α activity in T cells using pharmacological inhibitors induced T cell activation, thus improving its cytotoxic activity on cancer cells (33,38). Our study indicates that knockdown of DGK kinases in myeloma cells increases sensitivity to T cells.…”

Section: Bcma Car-t Cell Co-culture Screen Reveals Myeloma Cell-intrisupporting

confidence: 59%

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

Ramkumar

Abarientos

Tian

et al. 2019

Preprint

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Cancer cells commonly develop resistance to immunotherapy by loss of antigen expression. Combinatorial treatments that increase levels of the target antigen on the surface of cancer cells have the potential to restore efficacy to immunotherapy. Here, we use our CRISPR interference and CRISPR activation-based functional genomics platform to systematically identify pathways controlling cell-surface expression of the multiple myeloma immunotherapy antigen - B cell maturation antigen, BCMA. We discovered that pharmacological inhibition of HDAC7 and the Sec61 complex increased cell-surface BCMA, including in primary patient cells. Importantly, pharmacological Sec61 inhibition enhanced the anti-myeloma efficacy of a BCMA-targeted antibody-drug conjugate. A CRISPR interference CAR-T coculture screen enabled us to identify both antigen-dependent and -independent mechanisms controlling response of myeloma cells to BCMA-targeted CAR-T cells. Thus, our study demonstrates the potential of CRISPR screens to uncover mechanisms controlling response of cancer cells to immunotherapy and to suggest potential combination therapies.Key PointsUsing CRISPR screens, we systematically identify mechanisms increasing expression of the immunotherapy target BCMA and ADC efficacy.We also identify antigen-independent mechanisms regulating response of cancer cells to BCMA-CAR-T cells.

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Section: Bcma Car-t Cell Co-culture Screen Reveals Myeloma Cell-intrisupporting

confidence: 59%

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

Ramkumar

Abarientos

Tian

et al. 2019

Preprint

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“…These include therapies that target other immune checkpoint receptors such as Tim3 and Lag3 (2), or other inhibitory receptors including the adenosine 2A receptor, prostaglandin E 2 (PGE 2 ) receptor, and TGFβ receptor complex (7, 8). Recently, interest has developed regarding the possibility of targeting intracellular inhibitory proteins to improve T cell activity against cancer, including diacylglycerol kinase ζ (DGKζ) (9, 10), and Casitas b-lineage proto-oncogene b (Cbl-b) (11), which attenuate signal transduction events downstream of the T cell receptor (TCR) and CD28. Targeting these proteins may be superior to targeting cell surface proteins, since their elimination confers simultaneous insensitivity to multiple cell surface inhibitory receptors.…”

Section: Introductionmentioning

confidence: 99%

Diacylglycerol Kinase ζ (DGKζ) and Casitas b-Lineage Proto-Oncogene b–Deficient Mice Have Similar Functional Outcomes in T Cells but DGKζ-Deficient Mice Have Increased T Cell Activation and Tumor Clearance

Wesley

McAllister

et al. 2018

ImmunoHorizons

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Targeting negative regulators downstream of the T cell receptor (TCR) represents a novel strategy to improve cancer immunotherapy. Two proteins that serve as critical inhibitory regulators downstream of the TCR are diacylglycerol kinase ζ (DGKζ), a regulator of Ras and PKC-θ signaling, and Casitas b-lineage proto-oncogene b (Cbl-b), an E3 ubiquitin ligase that predominantly regulates PI(3)K signaling. We sought to compare the signaling and functional effects that result from deletion of DGKζ, Cbl-b, or both (double knockout, DKO) in T cells, and to evaluate tumor responses generated in a clinically relevant orthotopic pancreatic tumor model. We found that whereas deletion of Cbl-b primarily served to enhance NF-κB signaling, deletion of DGKζ enhanced TCR-mediated signal transduction downstream of Ras/Erk and NF-κB. Deletion of DGKζ or Cbl-b comparably enhanced CD8+ T cell functional responses, such as proliferation, production of IFNγ, and generation of granzyme B when compared with WT T cells. DKO T cells demonstrated enhanced function above that observed with single knockout T cells after weak, but not strong, stimulation. Deletion of DGKζ, but not Cbl-b, however, resulted in significant increases in numbers of activated (CD44hi) CD8+ T cells in both non-treated and tumor-bearing mice. DGKζ-deficient mice also had enhanced control of pancreatic tumor cell growth compared to Cbl-b-deficient mice. This represents the first direct comparison between mice of these genotypes and suggests that T cell immunotherapies may be better improved by targeting TCR signaling molecules that are regulated by DGKζ as opposed to molecules regulated by Cbl-b.

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“…In this study, we analyzed the antitumor efficacy of T cells that are deficient in diacylglycerol kinase zeta (DGKz), which is a key regulator of the cell membrane lipid diacylglycerol (DAG). DGKs are a family of proteins that phosphorylate DAG, resulting in decreased levels of this molecule, which is important in lipid biochemistry and signal transduction in eukaryotic cells (6,7). In T cells, DAG functions as an important second messenger, participating in the activation of RasGRP1 and PKCq after stimulation of the T-cell receptor (TCR; ref.…”

Section: Introductionmentioning

confidence: 99%

T Cells Deficient in Diacylglycerol Kinase ζ Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia

et al. 2017

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Efforts to improve the efficacy of adoptive T-cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the antileukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKζ T cells relied partly on induction of sustainable host T-cell immunity. Transferring DGKζ-deficient T cells increased the levels of IFNγ and other cytokines in recipient mice, especially with coadministration of anti-PD-L1. Overall, our results offered evidence that targeting DGKζ may leverage the efficacy of adoptive T-cell and immune checkpoint therapies in leukemia treatment. Furthermore, they suggest that DGKζ targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade. .

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Diacylglycerol Kinases (DGKs): Novel Targets for Improving T Cell Activity in Cancer

Cited by 50 publications

References 63 publications

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

Diacylglycerol Kinase ζ (DGKζ) and Casitas b-Lineage Proto-Oncogene b–Deficient Mice Have Similar Functional Outcomes in T Cells but DGKζ-Deficient Mice Have Increased T Cell Activation and Tumor Clearance

T Cells Deficient in Diacylglycerol Kinase ζ Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia

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