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

ImmunoHorizons
Erin WesleyMatthew J Riese

Abstract

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 (CD4...Continue Reading

Citations

Nov 24, 2019·International Journal of Molecular Sciences·Poojitha SitaramMatthew J Riese
Jul 2, 2020·Clinical Science·Gianluca BaldanziMario Malerba
Nov 29, 2020·Journal for Immunotherapy of Cancer·Javier Arranz-NicolásIsabel Merida
Dec 12, 2020·Clinical and Experimental Immunology·D JafariA Esmaeilzadeh
Apr 11, 2021·Cancer Immunology, Immunotherapy : CII·Javier Arranz-NicolásIsabel Merida

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