Enhanced effector responses in activated CD8+ T cells deficient in diacylglycerol kinases. Cancer Res 2013 Jun 15;73(12):3566-77
Date
04/12/2013Pubmed ID
23576561Pubmed Central ID
PMC3686869DOI
10.1158/0008-5472.CAN-12-3874Scopus ID
2-s2.0-84879097325 (requires institutional sign-in at Scopus site) 105 CitationsAbstract
Recent clinical trials have shown promise in the use of chimeric antigen receptor (CAR)-transduced T cells; however, augmentation of their activity may broaden their clinical use and improve their efficacy. We hypothesized that because CAR action requires proteins essential for T-cell receptor (TCR) signal transduction, deletion of negative regulators of these signaling pathways would enhance CAR signaling and effector T-cell function. We tested CAR activity and function in T cells that lacked one or both isoforms of diacylglycerol kinase (dgk) expressed highly in T cells, dgkα and dgkζ, enzymes that metabolize the second messenger diacylglycerol (DAG) and limit Ras/ERK activation. We found that primary murine T cells transduced with CARs specific for the human tumor antigen mesothelin showed greatly enhanced cytokine production and cytotoxicity when cocultured with a murine mesothelioma line that stably expresses mesothelin. In addition, we found that dgk-deficient CAR-transduced T cells were more effective in limiting the growth of implanted tumors, both concurrent with and after establishment of tumor. Consistent with our studies in mice, pharmacologic inhibition of dgks also augments function of primary human T cells transduced with CARs. These results suggest that deletion of negative regulators of TCR signaling enhances the activity and function of CAR-expressing T cells and identify dgks as potential targets for improving the clinical potential of CARs.
Author List
Riese MJ, Wang LC, Moon EK, Joshi RP, Ranganathan A, June CH, Koretzky GA, Albelda SMMESH terms used to index this publication - Major topics in bold
AnimalsBlotting, Western
CD8-Positive T-Lymphocytes
Cell Line, Tumor
Cells, Cultured
Diacylglycerol Kinase
Diglycerides
Flow Cytometry
GPI-Linked Proteins
HEK293 Cells
Humans
Immunotherapy, Adoptive
Isoenzymes
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasms, Experimental
Receptors, Antigen, T-Cell
Signal Transduction
