Diacylglycerol kinase ? (DGK?) and Casitas b-lineage proto-oncogene b-deficient mice have similar functional outcomes in T cells but DGK?-deficient mice have increased T cell activation and tumor clearance.

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 ? (DGK?), a regulator of Ras and PKC-? 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 DGK?, 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-?B signaling, deletion of DGK? enhanced TCR-mediated signal transduction downstream of Ras/Erk and NF-?B. Deletion of DGK? or Cbl-b comparably enhanced CD8+ T cell functional responses, such as proliferation, production of IFN?, 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 DGK?, 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. DGK?-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 DGK? as opposed to molecules regulated by Cbl-b.

SUBMITTER: Wesley EM 

PROVIDER: S-EPMC6048965 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature