T Cells Deficient in Diacylglycerol Kinase ζ Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia.

Weiqing Jing,Laura Mcolash,James Weber,Jill A Gershan,Erin Wesley,Sridhar Rao,Matthew J Riese,Kirthi Pulakanti,Katie Palen,Bryon D Johnson,Sandra Holzhauer

doi:10.1158/0008-5472.can-17-1309

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.

Highlights

T cells are capable of recognizing and eliminating cancer cells, there are multiple cancer-induced regulatory mechanisms that contribute to immune suppression, including the production of immune inhibitory factors and deficiencies in T-cell priming and activation that prevent effective antitumor immunity
When percentages of CD8þSIY pentamerþ T cells were examined in the spleens, bone marrow, and livers of these mice, greater percentages of CD8þCD44hiSIYþ T cells were observed in DGKzÀ/À mice as compared with WT mice (Fig. 1B and C)
To determine reactivity to tumor antigens, ACT donor (CD45.2þ) and endogenous host (CD45.1þ) CD8þ T cells were sorted by flow cytometry and tested for reactivity to C1498.SIY leukemia cells, in IFNg enzyme-linked immunosorbent spot (ELISPOT) assays

Summary

Introduction

T cells are capable of recognizing and eliminating cancer cells, there are multiple cancer-induced regulatory mechanisms that contribute to immune suppression, including the production of immune inhibitory factors (arginase, cyclooxygenase 2, prostaglandin E2, indoleamine 2,3 dioxygenase, TGFb, IL10) and deficiencies in T-cell priming and activation (lack of immunogenic neo-tumor antigens, downregulation of MHC molecules, ineffective antigen processing and presentation by antigen-presenting cells, and upregulation of inhibitory receptors on T cells) that prevent effective antitumor immunity. Mechanisms that facilitate either the lack of response or development of resistance to checkpoint inhibition are poorly understood, but any of the several cancer-induced or T-cell– intrinsic immunosuppressive mechanisms may play a role. The use of adoptively transferred T cells to induce a host immune response against tumor has not been extensively evaluated and may represent a strategy that complements the use of immune checkpoint inhibition

Objectives

Methods

Results

Conclusion