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

T-cell dysfunction is a hallmark of B-cell Chronic Lymphocytic Leukemia (CLL), where CLL cells downregulate T-cell responses through 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 responses to ICB. Since CLL IL-10 expression depends on Sp1, we utilized a novel, better tolerated analogue of the Sp1 inhibitor mithramycin (MTM(ox)32E) to suppress CLL IL-10. MTM(ox)32E treatment inhibited mouse and human CLL IL-10 production and maintained T-cell effector function in vitro. In the E mu-Tcl1 mouse model, treatment reduced plasma IL-10 and CLL burden and increased CD8(+) T-cell proliferation, effector and memory cell prevalence, and interferon-gamma 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 to anti-PD-L1 alone. Combination therapy also produced more interferon-gamma(+), cytotoxic effector KLRG1(+), and memory CD8(+) T-cells, and fewer exhausted T-cells. Since current therapies for CLL do not target IL-10, this provides a novel strategy to improve immunotherapies.

Automated summary

In CLL, T-cell dysfunction is driven by molecules like PD-L1 and IL-10. Suppressing IL-10 using a novel inhibitor enhances antitumor T-cell activity and responses to ICB. Targeting IL-10 provides a novel strategy to improve immunotherapies in CLL patients who do not respond well to current therapies.