Faculty Collaboration Database

T Cells Deficient in Diacylglycerol Kinase ζ Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia. Cancer Res 2017 Oct 15;77(20):5676-5686

Date

09/17/2017

Pubmed ID

28916658

DOI

10.1158/0008-5472.CAN-17-1309

Scopus ID

2-s2.0-85031429221 (requires institutional sign-in at Scopus site)   14 Citations

Abstract

Efforts to improve the efficacy of adoptive T-cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the antileukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ^-/-) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKζ^-/- T cells relied partly on induction of sustainable host T-cell immunity. Transferring DGKζ-deficient T cells increased the levels of IFNγ and other cytokines in recipient mice, especially with coadministration of anti-PD-L1. Overall, our results offered evidence that targeting DGKζ may leverage the efficacy of adoptive T-cell and immune checkpoint therapies in leukemia treatment. Furthermore, they suggest that DGKζ targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade. Cancer Res; 77(20); 5676-86. ©2017 AACR.

Author List

Jing W, Gershan JA, Holzhauer S, Weber J, Palen K, McOlash L, Pulakanti K, Wesley E, Rao S, Johnson BD, Riese MJ

Authors

Bryon D. Johnson PhD Adjunct Professor in the Medicine department at Medical College of Wisconsin
Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
B7-H1 Antigen
Diacylglycerol Kinase
Immunotherapy, Adoptive
Leukemia
Mice
Mice, Inbred C57BL
Mice, Transgenic
Programmed Cell Death 1 Receptor
Signal Transduction
T-Lymphocytes