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Figure 1. The chronic lymphocytic leukemia microenvironment. In the tumor microenvironment (TME) of chronic lymphocytic leukemia (CLL) patients, T cells and B cells interact with each other. The CLL cells provide soluble factors and cell-cell interactions to suppress T-cell function and the T cells provide soluble factors and cell-cell interactions to sustain CLL cells. BCR: B-cell receptor, TLR: Toll-like receptor, Bcl-2: B-cell lymphoma-2, Bfl-1: Bcl2 related protein A1, Bcl-XL: B-cell lymphoma- extra large, Mcl-1: induced myeloid leukemia cell differentiation protein, IL-4: interleukin-4, IL-21: interleukin-21, IFNγ: interferon-gamma, IL-10: interleukin-10, TBG- β: transforming growth factor-beta, PD-1: programmed death protein-1
T-cell dysfunction in CLL
addition, CLL cells enforce immunosuppression by the production of IL-10. As described below, T cells from CLL patients develop a dysfunctional phenotype.
Over the last decade, the mobilization of host T-cell responses to combat their cancer pathogenesis has revolu- tionized therapy. Strategies to reinforce an autologous immune response based on cellular cytotoxicity include immune checkpoint blockade (ICB), such as the pro- grammed cell death protein-1 (PD-1) targeting agents, chimeric antigen receptor (CAR) T-cell therapeutic approaches and bi-specific antibody-derived constructs.12 These strategies direct T cells to the malignant cells and have been effective in a variety of neoplasms including hematological malignancies.13,14 Despite high expectations in CLL, results of clinical trials have been disappointing. For example, effective PD-1 blockade was only observed for patients with Richter’s transformation;15 demonstrat- ing that targeting the PD-1/PDL-1 axis is not sufficient to rescue T-cell dysfunction in CLL patients and that other mechanisms are involved. It has been suggested that there is involvement of a novel metabolic immune checkpoint, IL4I1, in resistance to ICB, as IL4I1 expressed on CLL cells suppresses the adaptive immune responses in a murine CLL model.16 CAR T-cell therapies have been developed against the CD19 antigen, expressed by CLL cells as well as healthy B cells.1 CD19-CAR T cells have induced durable response albeit in a small fraction of CLL patients.14,17 Since CAR T cells are generated from autolo-
gous T cells, it is likely that CLL-induced T-cell dysfunc- tion may contribute to suboptimal results in patients. The generation of CAR T cells provides a window-of-opportu- nity to optimize these cells, either by specific culture con- ditions or additional genetic editing. In order for this to succeed, it is essential to understand the underlying mech- anisms of dysfunction.
Epigenetic mechanisms regulate cell differentiation and function by modulating gene expression patterns (Table 1). A disrupted and unstable epigenome is often described in cancer18 and has received widespread attention in virtu- ally all types of malignancies, including CLL,19,20 and tech- nological advances allow epigenomic profiling on a genome-wide scale from low cell numbers. In addition, bioinformatic tools facilitate easier integration across dif- ferent omics platforms. In CLL, this has led to studies of DNA methylation, histone modifications and chromatin accessibility for the purpose of understanding clinical behavior and cellular origin.19,21 Similarly, in non-malignant T-cell research these same technologies have been har- nessed to study cellular differentiation.22 Advances in immunotherapy are accompanied by an increasing need to understand the epigenome of the dysfunctional and exhausted T cell,23 a research area that is unexplored in CLL T cells.24,25
The aim of this review is to examine the literature on epigenetic mechanisms of T-cell function and dysfunction, thereby posing a number of critical questions on the
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