T cells are functionally not impaired in AML: increased PD-1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment.

Frauke M Schnorfeil,Rika Draenert,Julia S Neitz,Wolfgang Hiddemann,Felix S Lichtenegger,Miriam Schlueter,Katharina Emmerig,Marion Subklewe

doi:10.1186/s13045-015-0189-2

Frauke M Schnorfeil, Rika Draenert + Show 6 more

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https://doi.org/10.1186/s13045-015-0189-2

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Abstract

BackgroundT cell function is crucial for the success of several novel immunotherapeutic strategies for the treatment of acute myeloid leukemia (AML). However, changes in phenotype and function of T cells have been described in various hematologic malignancies, mimicking T cell exhaustion known from chronic viral infections. Detailed knowledge about phenotype and function of T cells in AML patients at different stages of the disease is indispensable for optimal development and application of immunotherapeutic strategies for this disease.MethodsWe used flow cytometry-based assays to characterize T cell phenotype and function in peripheral blood and bone marrow of AML patients at diagnosis, at relapse after intensive chemotherapy, and at relapse after allogeneic stem cell transplantation (SCT). Surface expression of CD244, PD-1, CD160, and TIM-3 was determined, and proliferation and production of IFN-γ, TNF-α, and IL-2 were measured.ResultsWe detected similar expression of inhibitory molecules on T cells from patients at diagnosis and from age-matched healthy controls. At relapse after SCT, however, PD-1 expression was significantly increased compared to diagnosis, both on CD4+ and CD8+ T cells. This pattern was not associated with age and cytomegalovirus (CMV) status but with a shift towards effector memory cells in relapsed AML patients. Proliferation and cytokine production assays did not reveal functional defects in T cells of AML patients, neither at diagnosis nor at relapse.ConclusionWe thus conclude that T cell exhaustion does not play a major role in AML. Immunotherapeutic strategies targeting autologous T cells thus have particularly good prospects in the setting of AML.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0189-2) contains supplementary material, which is available to authorized users.

Highlights

T cell function is crucial for the success of several novel immunotherapeutic strategies for the treatment of acute myeloid leukemia (AML)
Increased levels of CD244, PD-1, CD160, and TIM-3 were expressed on peripheral blood CD8+ and CD4+ T cells of untreated human immunodeficiency virus (HIV) patients compared to healthy controls CD244, PD-1, CD160, and TIM-3 are the most prominent inhibitory molecules upregulated in the context of T cell exhaustion
CD8+ T cells of younger (≤40 years) HIV patients showed a strong increase in expression levels compared to the respective healthy controls (HC) for CD244, PD-1, and CD160

Summary

Introduction

T cell function is crucial for the success of several novel immunotherapeutic strategies for the treatment of acute myeloid leukemia (AML). Different degrees of T cell dysfunctionality have been described in various hematologic malignancies, including adult T cell leukemia/lymphoma [12, 13], chronic myeloid leukemia [14, 15], and chronic lymphoid leukemia (CLL) [16,17,18] These observations have recently been put into the context of T cell exhaustion, a state of T cell dysfunction that is defined by increased expression of several inhibitory receptors (CD244, PD-1, CD160, TIM-3, LAG-3) in combination with poor effector function (hypoproliferation, diminished cytokine production, impaired cytotoxicity) and apoptosis [19]. Most of the data has been gathered on CD8+ T cells, but loss of effector function has been described in virusspecific CD4+ T cells [26, 27]

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