CD28 Superagonistic Activation of T Cells Induces a Tumor Cell-Like Metabolic Program.

Thilipan Thaventhiran,Ahmad F Alghanem,Steven D Webb,Mohammad A Aljasir,Wai Wong,Laiche Djouhri,Amy E Chadwick,Simeon Ramsey,Han Xian Aw Yeang,Michael Cross,Christina Ball,Naif Alhumeed,Swaminathan Sethu,Jean G Sathish,Richard Stebbings

doi:10.1089/mab.2018.0042

Abstract

CD28 superagonist (CD28SA), a therapeutic immunomodulatory monoclonal antibody triggered rapid and exaggerated activation of CD4+ effector memory T cells (TEMs) in humans with unwanted serious adverse effects. It is well known that distinct metabolic programs determine the fate and responses of immune cells. In this study, we show that human CD4+ TEMs stimulated with CD28SA adopt a metabolic program similar to those of tumor cells with enhanced glucose utilization, lipid biosynthesis, and proliferation in hypoxic conditions. Identification of metabolic profiles underlying hyperactive T cell activation would provide a platform to test safety of immunostimulatory antibodies.

Highlights

C D28 superagonists (CD28SAs) are monoclonal antibodies that engage CD28 costimulatory receptors resulting in potent T cell activation independent of concomitant T cell receptor (TCR) engagement.[1]. TGN1412, a CD28 superagonist (CD28SA), triggered an excessive and adverse cytokine release when administered to volunteers in a human Phase 1 clinical trial.[2]. We and others have shown that CD28SA induces exaggerated activation, polyclonal expansion, and migration of CD4+ effector memory T cells (TEMs).(2–4) The basis for this hyperactive, dysregulated phenotype is subject of much research and the lack of inhibitory inputs[4] has been suggested as one potential mechanism
The metabolic programming of T cells is an area of intense investigation with implications for therapeutic intervention in many disease areas.[13,14,15,16] We and others have previously shown that CD28SA activation results in a hyperactive T cell phenotype.[4,17] Activated immune cells prefer glycolysis over oxidative phosphorylation (OXPHOS) as it is around two orders of magnitude faster for biomass accumulation and proliferation.[18]. OXPHOS is necessary for cell-surface expression of the IL-2 receptor and vital for lymphocyte proliferation.[19]
We find that CD28SA-stimulated TEMs cells had higher levels of ATP production, basal respiration, and actively respiring mitochondria compared with antiCD3-activated TEMs

Summary

Introduction

C D28 superagonists (CD28SAs) are monoclonal antibodies (mAbs) that engage CD28 costimulatory receptors resulting in potent T cell activation independent of concomitant T cell receptor (TCR) engagement.[1]. T cells adopt a metabolic profile typified by aerobic glycolysis and basal oxidative phosphorylation (OXPHOS).(5,7) Rapidly proliferating T cells require lipids to support membrane biogenesis and depending on the T cell subset, lipids may be acquired or synthesized (lipogenesis).(8) T cells use distinct metabolic programs according to their differentiation state and immunological role. Studies have shown that CD4+ T helper (Th), Th2, and Th17 cells are highly glycolytic, whereas CD4+ regulatory T cells have high lipid oxidation rates.[9] The metabolic phenotype of the TGN1412-target cell, CD4+ TEMs, is yet to be fully characterized. Tumor cells exhibit metabolic abnormalities such as elevated aerobic glycolysis and de novo fatty acid biosynthesis to generate the energy required to support rapid cell division.[10] In this report, we demonstrate that superagonistic activation programs CD4+ TEMs toward a tumor cell-like metabolic profile that favors enhanced glycolysis and lipogenesis. We define ATP-citrate lyase (ACL) and acetylCoenzyme A (ACC) as key molecular indicators of the CD28SA-induced lipogenic phenotype

Materials and Methods

Results

Discussion

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