Immuno-regulatory malignant B cells contribute to Chronic Lymphocytic Leukemia progression

Abstract

Chronic Lymphocytic Leukemia (CLL) is a heterogeneous B cell neoplasm ranging from indolent to rapidly progressive disease. Leukemic cell subsets with regulatory properties evade immune clearance; however, the contribution of such subsets during CLL progression is not completely elucidated. Here, we report that CLL B cells crosstalk with their immune counterparts, notably by promoting the regulatory T (Treg) cell compartment and shaping several helper T (Th) subsets. Among various constitutively- and BCR/CD40-mediated factors secreted, tumour subsets co-express two important immunoregulatory cytokines, IL10 and TGFβ1, both associated with a memory B cell phenotype. Neutralizing secreted IL10 or inhibiting the TGFβ signalling pathway demonstrated that these cytokines are mainly involved in Th- and Treg differentiation/maintenance. In line with the regulatory subsets, we also demonstrated that a CLL B cell population expresses FOXP3, a marker of regulatory T cells. Analysis of IL10, TGFβ1 and FOXP3 positive subpopulations frequencies in CLL samples discriminated 2 clusters of untreated CLL patients that were significantly different in Tregs frequency and time-to-treatment. Since this distinction was pertinent to disease progression, the regulatory profiling provides a new rationale for patient stratification and sheds light on immune dysfunction in CLL.

Targeting T regulatory (Treg) cells in immunotherapy-resistant cancers

“…Interestingly, this reduction in T reg cells seemed to coincide with toxicities reminiscent of autoimmune toxicities observed in patients receiving ICI [ 126 ] . Therefore, treatments with oral PI3K-δ inhibitors have offered new insights into the role of T reg cells or their mediators, such as the underappreciated role of IL-17 [ 127 - 129 ] . Whether this effect of PI3K-δ inhibitors is uniquely related to the reduction in T reg cells remains to be determined, because a reduction or inhibition of the function of T reg cells is not always associated with autoimmune toxicities.…”

Cross‐talk between leukemic and immune cells at the tumor microenvironment in chronic lymphocytic leukemia: An update review

“…106 Bregs exhibit immunosuppressive characteristics that could inhibit efficient anti CLL immunity, which may help to explain some of the immunosuppressive aspects of CLL cells that are already recognized. 4,107 Interestingly, CLL B cells and Breg share a number of phenotypic properties, including the expression of CD27, CD24, and CD5 as well as low levels of surface IgM. 106 Similar to Breg cells, CLL cells secrete remarkable amounts of IL-10 after in vitro stimulation with TLR9 agonist or CD40L.…”

Analysis of Mutational Status of IGHV, and Cytokine Polymorphisms as Prognostic Factors in Chronic Lymphocytic Leukemia: The Romanian Experience

“…Additionally, IL-10 has both stimulatory and suppressive functions in T lymphocytes. Some studies suggest that IL-10 suppresses cancer cells by stimulating CD8+ T cells, while other research indicates that IL-10 can lead to the stimulation of tumor cell proliferation [25][26][27][28][29][30][31][32].…”

“…The IL-10 gene ranks within the top 1% of the most highly differentially methylated genes between unmutated CLL (U-CLL) and mutated CLL (M-CLL), being hypomethylated in M-CLL. Consequently, M-CLL produces more IL-10 than U-CLL following TLR receptor stimulation [26,34,35]. Moreover, IL-10 production in M-CLL cases has been correlated with reduced immune activity [26,27].…”

“…Consequently, M-CLL produces more IL-10 than U-CLL following TLR receptor stimulation [26,34,35]. Moreover, IL-10 production in M-CLL cases has been correlated with reduced immune activity [26,27].…”