Journal
LEUKEMIA
Volume 35, Issue 11, Pages 3188-3200Publisher
SPRINGERNATURE
DOI: 10.1038/s41375-021-01217-1
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Funding
- NCI Training Grant [T32CA165990]
- National Center for Advancing Translational Sciences [UL1TR001998, UL1TR000117]
- Center of Biomedical Research Excellence (COBRE) in Pharmaceutical Research and Innovation (CPRI) [P20GM130456]
- University of Kentucky College of Pharmacy PharmNMR Center
- University of Kentucky Markey Cancer Center
- Markey Cancer Center's Flow Cytometry and Immune Monitoring Shared Resource Facility [P30CA177558]
- [R01CA165469]
- [R01CA217934]
- [R01CA217255]
- [R01GM115261]
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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.
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.
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