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

Abstract

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.

BTLA/HVEM Axis Induces NK Cell Immunosuppression and Poor Outcome in Chronic Lymphocytic Leukemia

“…Further, as previously reported, BTLA blockade decreased the production of the immunosuppressive and tumor-promoting cytokine IL-10 by B cells, suggesting that targeting BTLA signaling may restore, at least in part, NK cell immune competence [ 48 , 68 , 69 , 70 ]. Importantly, a recent work has showed that inhibition of IL-10 boosts ICB-related anti-tumor responses in CLL [ 71 ]. In line with this, BTLA blockade promoted NK cell-mediated cytotoxicity and rituximab-induced ADCC in CLL.…”

PKCβ facilitates leukemogenesis in chronic lymphocytic leukaemia by promoting constitutive BCR-mediated signaling

“…This notion is supported by recent work showing that targeted delivery of miR-29b to CLL cells leads to enhanced cellular reprogramming and decreased viability due to its effect of decreasing SP1 expression [31]. Furthermore, mtm analogs have been shown to be effective against CLL cells, with EC-7072 inducing CLL cell death through targeting of BCR signaling [32], and administration of MTM OX 32E to the Eμ-Tcl1 mouse model reduces the malignant cell burden [33].…”

Antigen-Specific TCR-T Cells for Acute Myeloid Leukemia: State of the Art and Challenges

“…As a tumor progresses, high levels of IL-10 exhibit powerful immunosuppressive effects through inhibiting the proliferation of T cells and the production of cytokines such as IFN-γ and IL-2 ( 159 ). IL-10 suppression was found to enhance the antitumor activity against CLL ( 161 ). In addition, combining T-cell therapy with treatments targeting immune cell PD-1 showed high efficacy against leukemia via the production of more IFN-γ, the increasing of cytolytic functions, and the increasing of memory CD8 + T cells ( 161 ).…”

“…IL-10 suppression was found to enhance the antitumor activity against CLL ( 161 ). In addition, combining T-cell therapy with treatments targeting immune cell PD-1 showed high efficacy against leukemia via the production of more IFN-γ, the increasing of cytolytic functions, and the increasing of memory CD8 + T cells ( 161 ).…”