Diacylglycerol kinase α inactivation is an integral component of the costimulatory pathway that amplifies TCR signals

Abstract

The arsenal of cancer therapies has evolved to target T lymphocytes and restore their capacity to destroy tumor cells. T cells rely on diacylglycerol (DAG) to carry out their functions. DAG availability and signaling are regulated by the enzymes diacylglycerol kinase (DGK) α and ζ, whose excess function drives T cells into hyporesponsive states. Targeting DGKα is a promising strategy for coping with cancer; its blockade could reinstate T-cell attack on tumors while limiting tumor growth, due to positive DGKα functions in several oncogenic pathways. Here, we made a side-by-side comparison of the effects of commercial pharmacological DGK inhibitors on T-cell responses with those promoted by DGKα and DGKζ genetic deletion or silencing. We show the specificity for DGKα of DGK inhibitors I and II and the structurally similar compound ritanserin. Inhibitor treatment promoted Ras/ERK (extracellular signal-regulated kinase) signaling and AP-1 (Activator protein-1) transcription, facilitated DGKα membrane localization, reduced the requirement for costimulation, and cooperated with enhanced activation following DGKζ silencing/deletion. DGKiII and ritanserin had similar effects on TCR proximal signaling, but ritanserin counteracted long-term T-cell activation, an effect that was potentiated in DGKα−/− cells. In contrast with enhanced activation triggered by pharmacological inhibition, DGKα silencing/genetic deletion led to impaired Lck (lymphocyte-specific protein tyrosine kinase) activation and limited costimulation responses. Our results demonstrate that pharmacological inhibition of DGKα downstream of the TCR provides a gain-of-function effect that amplifies the DAG-dependent signaling cascade, an ability that could be exploited therapeutically to reinvigorate T cells to attack tumors.

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Abbreviations

5-HT:

Serotonin

5-HTR:

Serotonin receptor

AP-1:

Activator protein-1

CNB:

Centro Nacional de Biotecnología

CSIC:

Consejo Superior de Investigaciones Científicas

DAG:

Diacylglycerol

DGK:

Diacylglycerol kinase

DGKi:

DGK inhibitor

ERK:

Extracellular signal-regulated kinase

HM-1:

Human muscarinic receptor-1

Lck:

Lymphocyte-specific protein tyrosine kinase

NFAT:

Nuclear factor of activated T cells

PLC:

Phospholipase C-gamma

WT:

Wild type

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Acknowledgements

We thank Rosa Liébana for maintenance of the mouse colonies and technical assistance in the isolation of mouse cells, Alejandra Cordero for technical assistance, Carmen Moreno for technical assistance in cytometry data acquisition, and Catherine Mark for excellent editorial assistance.

Funding

Javier Arranz-Nicolás and Jesús Ogando hold predoctoral FPI fellowships from the Spanish Ministry of Economy and Competitiveness (MINECO). This work was supported in part by grants from the MINECO/FEDER/EU (BFU2016-77207-R), Spanish Ministry of Health (Instituto de Salud Carlos III; RD12/0036/0059) to Isabel Mérida, MINECO/FEDER/EU (SAF2017-83732-R) to Santos Mañes, and from the Madrid regional government (IMMUNOTHERCAM Consortium CM B2017/BMD3733) to Isabel Mérida and Santos Mañes.

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Authors

Contributions

Javier Arranz-Nicolás and Antonia Ávila-Flores performed mouse and Jurkat cell experiments, acquired, analyzed and interpreted data, and prepared the figures. Jesús Ogando performed the PBMC experiments and acquired the data. Jesús Ogando and Santos Mañes interpreted the PBMC data. Denise Soutar performed mouse experiments. Daniel Meraviglia-Crivelli and Raquel Arcos-Pérez performed Jurkat and mouse cells RT-PCR experiments. Raquel Arcos-Pérez developed the luciferase constructs. Antonia Ávila-Flores and Isabel Mérida designed and supervised the study, interpreted the data and wrote the manuscript. All authors read and gave input on the manuscript.

Corresponding authors

Correspondence to Isabel Mérida or Antonia Ávila-Flores.

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Conflict of interest

The authors declare no potential conflicts of interest.

Ethical approval

Mice were maintained and handled in accordance with Spanish and European directives. All procedures performed with animals were conducted according the protocols approved by the CNB/CSIC Ethics Committee on Animal Experimentation (RD53/2013). PBMC were from the Blood Transfusion Center, Red Cross (Madrid, Spain), obtained with appropriate informed consent from the donors. No personal data were registered and all procedures performed with these cells were in accordance with the ethical standards of the CNB/CSIC Ethics Committee.

Animal source

C57BL/6J-DGKα−/− mice were kindly donated by Dr. Xiao-Ping Zhong (Duke University Medical Center, Durham NC). C57BL/6J-DGKζ−/− mice were a gift of Dr. Gary Koretzky (University of Pennsylvania, Philadelphia PA). These mouse lines were used to generate the corresponding OT-I DGK−/− mice. The colonies were maintained in pathogen-free conditions in the CNB animal facility, following institutional guidelines.

Cell line authentication

Human leukemic Jurkat T cells were authenticated by polymorphic short tandem repeat (STR) locus analysis (Genomics Service, Centro de Investigaciones Biomédicas-CSIC).

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Arranz-Nicolás, J., Ogando, J., Soutar, D. et al. Diacylglycerol kinase α inactivation is an integral component of the costimulatory pathway that amplifies TCR signals. Cancer Immunol Immunother 67, 965–980 (2018). https://doi.org/10.1007/s00262-018-2154-8

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Keywords

  • Diacylglycerol kinase
  • Cancer immunotherapy
  • Lck
  • T-cell activation
  • R59949
  • Serotonin receptors