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Ferrata Storti Foundation
Haematologica 2021 Volume 106(5):1234-1243
T-cell dysfunction in chronic lymphocytic leukemia from an epigenetic perspective
Fleur S. Peters,1,2,3,4,5 Jonathan C. Strefford,6 Eric Eldering1,3,4,5 and Arnon P. Kater2,3,4,5
1Departments of Experimental Immunology, University of Amsterdam, Amsterdam, the Netherlands; 2Departments of Hematology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; 3Cancer Center Amsterdam, Amsterdam, the Netherlands; 4Amsterdam Institute of Infection and Immunity, Amsterdam, the Netherlands; 5Lymphoma and Myeloma Center Amsterdam, LYMMCARE, Amsterdam, the Netherlands and 6Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
ABSTRACT
Cellular immunotherapeutic approaches such as chimeric antigen receptor (CAR) T-cell therapy in chronic lymphocytic leukemia (CLL) thus far have not met the high expectations. Therefore it is essential to better understand the molecular mechanisms of CLL- induced T-cell dysfunction. Even though a significant number of studies are available on T-cell function and dysfunction in CLL patients, none examine dysfunction at the epigenomic level. In non-malignant T-cell research, epigenomics is widely employed to define the differentiation pathway into T-cell exhaustion. Additionally, metabolic restrictions in the tumor microenvironment that cause T-cell dysfunction are often mediated by epigenetic changes. With this review paper we argue that understanding the epigenetic (dys)regulation in T cells of CLL patients should be leveled to the knowledge we currently have of the neoplastic B cells themselves. This will permit a complete understanding of how these immune cell interactions regulate T- and B-cell function. Here we relate the cellular and phenotypic characteristics of CLL-induced T-cell dysfunction to epigenetic studies of T-cell regulation emerging from chronic viral infection and tumor models. This paper proposes a frame- work for future studies into the epigenetic regulation of CLL-induced T- cell dysfunction, knowledge that will help to guide improvements in the utility of autologous T-cell based therapies in CLL.
Introduction
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by the accumulation of CD5+ B cells in the bone marrow, spleen, lymph nodes (LN) and peripheral blood (PB).1 The disease course is heterogeneous; some patients require early treatment for progressive disease whilst others never require clinical interven- tion. Mutational status of the variable region of the immunoglobulin heavy chain (IGHV) gene reflects the stage of B-cell maturation from which the CLL cells orig- inate and is a powerful prognostic and predictive biomarker.2,3 These immuno- genetic studies are part of a great effort to identify the cell-of-origin of CLL subsets and thereby trace the differentiation path from normal to neoplastic B cells.4 A range of therapies are currently available for CLL. Whilst a proportion of patients can be successfully treated with chemo-immunotherapy and many achieve mean- ingful remissions during treatment with Ibrutinib and Venetoclax, patients eventu- ally develop resistance.5,6
CLL cells actively migrate to the LN to receive survival signals and interact with other cell types, including stromal cells, monocyte-derived macrophages and T cells,7 that provide soluble factors and cell-cell interactions. Within this tumor microenvironment (TME), CD40/CD40L interactions between CLL cells and T- helper cells (Th) induce tumor cell proliferation and upregulation of anti-apoptotic proteins (Figure 1).8 The T-cell derived cytokines interleukin-4 (IL-4), IL-21 and interferon-gamma (IFNγ), also promote CLL cell proliferation and survival.9–11 In
Correspondence:
FLEUR S. PETERS
f.s.peters@amsterdamumc.nl
Received: November 19, 2020. Accepted: February 18, 2021. Pre-published: March11,2021.
https://doi.org/10.3324/haematol.2020.267914
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