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, MTM ox 32E, to suppress CLL IL-10. We found MTM ox 32E inhibited mouse and human CLL IL-10 production and maintained Tcell 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.

IL-13Rα2 humanized scFv-based CAR-T cells exhibit therapeutic activity against glioblastoma

“…Our in vitro cell killing result indicated that this humanized third-generation CAR-targeting IL-13Rα2 did not secrete increased IL-6 and expressed dramatic low levels of IL-10. Since IL-6 was identified to be a key driver of CRS, 24 while IL-10 was found to induce T cell dysfunction, 25 our results suggest a powerful anti-GBM potential in patients.…”

IL-10 Signaling Elicited by Nivolumab-Induced Activation of the MAP Kinase Pathway Does Not Fully Contribute to Nivolumab-Modulated Heterogeneous T Cell Responses

“…The combination of anti-IL-10 with anti-PD-1 treatment in this model significantly inhibits tumor growth compared to treatment with either component alone [ 25 ]. Consistent with these observations, blocking IL-10 increases anti-tumor T cell activity and ICI responsiveness in a chronic lymphocytic leukemia mouse model [ 26 ]. Furthermore, in a phase II clinical trial, the serum levels of IL-10 prior to treatment have been shown to be associated with better efficacy in patients treated with nivolumab [ 27 , 28 ].…”

IL-10 Rescues CLL Survival through Repolarization of Inflammatory Nurse-like Cells

“…This is not in agreement with the fact that TNF favours the M1 macrophage phenotype, despite the current view of NLC being M2-polarized in the TME. On the other hand, IL-10 thwarts anti-tumoral immune responses, inhibits pro-inflammatory cytokines like TNF, and increases the level of pro-survival molecules such as ICAM-1 on the surface of CLL cells [ 26 , 27 , 28 ].…”