T-cell dysfunction in chronic lymphocytic leukemia from an epigenetic perspective

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 CLLinduced 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 framework for future studies into the epigenetic regulation of CLL-induced Tcell dysfunction, knowledge that will help to guide improvements in the utility of autologous T-cell based therapies in CLL.

Chronic lymphocytic leukemia presence impairs antigen-specific CD8+ T-cell responses through epigenetic reprogramming towards short-lived effectors

“…Epigenomic analyses are widely employed to understand T-cell dysfunction, yet how CLL in uences the Tcell epigenome is still unknown (7). We show extensive differences in OT-I cells from WT and TCL1 mice regarding chromatin accessibility, establishing that presence of leukemic cells during infection alters the T-cell epigenome.…”

“…Skewing of T-cell differentiation has been well described in CLL and is hallmarked by increasing absolute numbers of CD8 + T cells with progressive reductions of naive and accumulation of highly differentiated effector-memory subtypes(6). The development of naive T cells into memory and effector cell populations upon an antigenic stimulus follows progressive epigenetic changes that instruct unique gene expression pro les and functions (7). Ex vivo studies indicate that acquired T-cell dysfunction in CLL occurs through direct and indirect interaction with CLL cells(8-10).…”

Effects of ibrutinib on T-cell immunity in patients with chronic lymphocytic leukemia

“…Tumor microenvironment disorder and T-cell immune dysfunction are the main characteristics of CLL patients (37,109). Long-term ibrutinib treatment promotes the restoration of immunity, particularly T-cell immunity, consistent with improved clinical outcomes observed in CLL patients (3,42).…”

The Mysterious Actor—γδ T Lymphocytes in Chronic Lymphocytic Leukaemia (CLL)

“…Interactions between CD40-expressing leukaemic B cells and CD40 ligands (CD40L) on activated CD4+ T cells promotes the proliferation of CLL cells and the upregulation of anti-apoptotic proteins. Moreover, T cells provide pro-survival signals through soluble factors, such as interleukin-4 (IL-4) and interferon-gamma (IFN-γ), which upregulate anti-apoptotic Bcl-2 in CLL cells [ 20 , 21 ]. The T cell number is increased in the peripheral blood of CLL patients; in particular, the CD8+ T cell count rises, causing a decline in the CD4:CD8 ratio.…”