Chronic Lymphocytic Leukemia–Derived IL-10 Suppresses Antitumor Immunity

Alhakeem, Sara S.; McKenna, Mary K.; Oben, Karine Z.; Noothi, Sunil K.; Rivas, Jacqueline R.; Fleischman, Roger A.; Muthusamy, Natarajan; Bondada, Subbarao

doi:10.4049/jimmunol.1800241

Cited by 46 publications

(50 citation statements)

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“…The activity of the calcineurin inhibitor Tacrolimus (FK506) in suppressing early IL-10 response by B cells, allows speculating on the adoption of new strategies to modulate IL-10 production in specific pathological settings. In this regard, we identified similarities in the il-10 locus methylation profile between human PB IL-10-producing B cells and malignant B cells of CLL and MCL, which have been reported exploiting IL-10 synthesis to maintain an immunosuppressive environment permissive for clone expansion [9,27]. In conclusion, we propose to consider B cells presenting demethylation on eIL10rr or dIL10rr as bona fide B regs .…”

Section: Discussionsupporting

confidence: 62%

IL‐10‐producing B cells are characterized by a specific methylation signature

et al. 2019

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Among the family of regulatory B cells, the subset able to produce interleukin‐10 (IL‐10) is the most studied, yet its biology is still a matter of investigation. The DNA methylation profiling of the il‐10 gene locus revealed a novel epigenetic signature characterizing murine B cells ready to respond through IL‐10 synthesis: a demethylated region located 4.5 kb from the transcription starting site (TSS), that we named early IL10 regulatory region (eIL10rr). This feature allows to distinguish B cells that are immediately prone and developmentally committed to IL‐10 production from those that require a persistent stimulation to exert an IL‐10‐mediated regulatory function. These late IL‐10 producers are instead characterized by a delayed IL10 regulatory region (dIL10rr), a partially demethylated DNA portion located 9 kb upstream from the TSS. A demethylated region was also found in human IL‐10‐producing B cells and, very interestingly, in some B‐cell malignancies, such as chronic lymphocytic leukemia and mantle cell lymphoma, characterized by an immunosuppressive microenvironment. Our findings define murine and human regulatory B cells as an epigenetically controlled functional state of mature B cell subsets and open a new perspective on IL‐10 regulation in B cells in homeostasis and disease.

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Section: Discussionsupporting

confidence: 62%

IL‐10‐producing B cells are characterized by a specific methylation signature

et al. 2019

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“…They reported that IL-10 affects CLL growth indirectly by suppressing anti-CLL T-cells. In their study IL-10 reduced the generation of effector CD4 and CD8 T-cells [19]. Still little is known about the mechanisms that lead to the increasing of M-MDSC, especially in the microenvironment of leukemia [20] and lymphoma [24].…”

Section: Discussionmentioning

confidence: 97%

“…Alhakeem et al [19] observed that CLL patients have a significantly higher level of IL-10 in plasma than healthy donors. They reported that IL-10 affects CLL growth indirectly by suppressing anti-CLL T-cells.…”

Section: Discussionmentioning

confidence: 99%

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Monocytic MDSC as a source of immunosuppressive cytokines in chronic lymphocytic leukemia (CLL) microenvironment

Kowalska

2020

Folia Histochem Cytobiol.

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Introduction. Myeloid derived suppressor cells (MDSCs) are one of the major components of the tumor microenvironment. The accumulation of MDSCs has been demonstrated in many types of human solid tumors. However, the relevance of this heterogeneous population in hematopoietic malignancies has only recently gained stronger attention. MDSCs are a phenotypically and functionally heterogeneous group of cells. The results of recent studies indicate that the immune dysregulation in chronic lymphocytic leukemia (CLL) affects a monocytic MDSC (M-MDSC) subpopulation. This study aimed to analyze the frequency of M-MDSCs with intracellular IL-10 and TGF-b1 expression in newly diagnosed CLL patients. We investigated the potential role of M-MDSCs in CLL by analyzing the level of IL-10 and TGF-b1 expression in circulating M-MDSCs in correlation with clinical and laboratory parameters characterizing disease activity and patients' immune status. Material and methods. Seventy CLL patients and 17 age-matched healthy volunteers were included in this study. Flow cytometric detection of Mo-MDSCs (CD14 + CD11b + CD15-HLA-DR-/low) with intracellular IL-10 and TGF-b1 expression was done. Results. We found a significantly higher median percentage of M-MDSC with IL-10 or TGF-b1 expression in CLL patients than in healthy volunteers. The percentage of M-MDSC with intracellular IL-10 or TGF-b1 expression was significantly lower in CLL patients at stage 0 as compared to the stages I/II and III/IV according to Rai stages. The percentage of M-MDSC with intracellular TGF-b1 expression was significantly higher in ZAP-70-positive and CD38-positive patients compared with ZAP-70-negative and group of CD38-negative ones. There was also a significantly higher percentage of M-MDSC positive for intracellular TGF-b expression in patients carrying the 11q22.3 and/or the 17p13.1 deletion than in patients without these genetic aberrations. The percentage of M-MDSC IL-10-positive and M-MDSC TGF-b1-positive measured at the time of diagnosis was higher in patients requiring therapy as compared to patients without treatment during the observation period. Conclusion. In conclusion, we have shown that an increased percentage of M-MDSC cells producing IL-10 and TGF-b1 in CLL patients may be associated with the suppression of the immune response against CLL. It can be assumed that the increased percentage of M-MDSC with an intracellular expression of IL-10 and TGF-b1 may be used in the future as the factor defining the group of patients with shorter time to onset of treatment.

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“…Since IL-10 is a well-known anti-inflammatory cytokine, we reasoned that CLLderived IL-10 also suppresses host antitumor T-cell responses (3,4). Members of the IL-10 cytokine family control immune responses in cancer, autoimmune conditions, and inflammatory diseases.…”

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confidence: 99%

Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia

Rivas

Alhakeem

Liu

et al. 2020

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T-cell dysfunction is a hallmark of B-cell Chronic Lymphocytic Leukemia (CLL). CLL cells downregulate T-cell responses by expressing regulatory molecules including programmed death ligand-1 (PD-L1) and Interleukin-10 (IL-10). Immune checkpoint blockade (ICB) aims to restore T-cell function by preventing the ligation of inhibitory receptors like PD-1, however most CLL patients do not respond well to this therapy. Thus, we investigated whether IL-10 suppression could enhance antitumor T-cell activity and improve responses to ICB. Since CLL IL-10 expression depends on Sp1, we utilized a novel, better tolerated mithramycin analogue, MTMox32E, to suppress CLL IL-10. We found MTMox32E inhibited mouse and human CLL IL-10 production and maintained T-cell effector function. In the Eμ-Tcl1 mouse model, treatment reduced plasma IL-10 and CLL burden while it increased CD8+ T-cell proliferation, effector and memory cell prevalence, and interferon-γ production. When combined with ICB, suppression of IL-10 improved responses to anti-PD-L1 as shown by a 4.5-fold decrease in CLL cell burden compared with anti-PD-L1 alone. Combination therapy also produced more interferon-γ+, cytotoxic effector KLRG1+, and memory CD8+ T-cells, with fewer exhausted T-cells than ICB alone. Since current therapies for CLL do not target IL-10, this provides a novel strategy to increase the efficacy of T-cell-based immunotherapies.

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Chronic Lymphocytic Leukemia–Derived IL-10 Suppresses Antitumor Immunity

Cited by 46 publications

References 46 publications

IL‐10‐producing B cells are characterized by a specific methylation signature

IL‐10‐producing B cells are characterized by a specific methylation signature

Monocytic MDSC as a source of immunosuppressive cytokines in chronic lymphocytic leukemia (CLL) microenvironment

Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia

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