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Expansion of Human Peripheral Blood γδ T Cells using Zoledronate
Published on: September 9, 2011
DGKα/ζ inhibition lowers the TCR affinity threshold and potentiates antitumor immunity
Rakeeb Kureshi1,2, Elisa Bello2,3, Courtney T S Kureshi1,2
1Department of Immunology, Harvard Medical School, Boston, MA, USA.
Abstract:
Diacylglycerol kinases (DGKs) attenuate diacylglycerol (DAG) signaling by converting DAG to phosphatidic acid, thereby suppressing pathways downstream of T cell receptor signaling. Using a dual DGKα/ζ inhibitor (DGKi), tumor-specific CD8 T cells with different affinities (TRP1high and TRP1low), and altered peptide ligands, we demonstrate that inhibition of DGKα/ζ can lower the signaling threshold for T cell priming. TRP1high and TRP1low CD8 T cells produced more effector cytokines in the presence of cognate antigen and DGKi. Effector TRP1high- and TRP1low-mediated cytolysis of tumor cells with low antigen load required antigen recognition, was mediated by interferon-γ, and augmented by DGKi. Adoptive T cell transfer into mice bearing pancreatic or melanoma tumors synergized with single-agent DGKi or DGKi and antiprogrammed cell death protein 1 (PD-1), with increased expansion of low-affinity T cells and increased cytokine production observed in tumors of treated mice. Collectively, our findings highlight DGKα/ζ as therapeutic targets for augmenting tumor-specific CD8 T cell function.
Insights
Inhibiting diacylglycerol kinases (DGKs) with a dual DGKα/ζ inhibitor lowers the T cell activation threshold. This approach enhances anti-tumor CD8 T cell responses, increasing cytokine production and tumor cell killing.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Diacylglycerol kinases (DGKs) regulate T cell receptor (TCR) signaling by phosphorylating diacylglycerol (DAG).
- DGKs attenuate DAG-mediated signaling pathways crucial for T cell activation and function.
- Targeting DGKs may offer a strategy to enhance anti-tumor immunity.
Purpose of the Study:
- To investigate the impact of dual DGKα/ζ inhibition on T cell priming and anti-tumor activity.
- To determine if DGK inhibition can lower the signaling threshold for T cell activation and effector function.
- To evaluate the therapeutic potential of DGK inhibitors in combination with other immunotherapies for cancer treatment.
Main Methods:
- Utilized a dual DGKα/ζ inhibitor (DGKi) in conjunction with tumor-specific CD8 T cells of varying affinities (TRP1high and TRP1low) and altered peptide ligands.
- Assessed T cell cytokine production (e.g., interferon-γ) and cytolytic activity against tumor cells.
- Conducted adoptive T cell transfer experiments in mouse models of pancreatic and melanoma tumors, combined with DGKi and anti-PD-1 therapy.
Main Results:
- DGKα/ζ inhibition reduced the signaling threshold for T cell priming, leading to enhanced effector cytokine production by both high- and low-affinity CD8 T cells.
- DGKi augmented antigen-specific cytolysis of tumor cells, particularly those with low antigen load, mediated by interferon-γ.
- Combined treatment with DGKi and anti-PD-1 synergized to increase the expansion of low-affinity T cells and boost cytokine production within tumors.
Conclusions:
- Dual DGKα/ζ inhibition is a promising strategy to enhance anti-tumor CD8 T cell responses.
- Targeting DGKα/ζ can improve T cell priming and effector functions, overcoming limitations in low-antigen environments.
- Combination therapy involving DGK inhibitors holds potential for augmenting cancer immunotherapy efficacy.
