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

• Published in: Leukemia Vol. 35; no. 11; pp. 3188 - 3200
• Main Authors: Rivas, J. R., Liu, Y., Alhakeem, S. S., Eckenrode, J. M., Marti, F., Collard, J. P., Zhang, Y., Shaaban, K. A., Muthusamy, N., Hildebrandt, G. C., Fleischman, R. A., Chen, L., Thorson, J. S., Leggas, M., Bondada, S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-11-2021; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/21; 13/31; 38/77; 631/250/1619/554/1834/1269; 631/250/251; 631/250/580; 631/67/1059/2325; 631/67/1990/283/1895; 64; 64/110; 64/60; Animals; Antibiotics, Antineoplastic - pharmacology; Anticancer properties; Antitumor activity; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; Cancer Research; Case-Control Studies; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; Chronic lymphocytic leukemia; Critical Care Medicine; Cytokines; Cytotoxicity; Development and progression; Disease Models, Animal; Drug therapy; Gene Expression Regulation, Neoplastic - drug effects; Health aspects; Hematology; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - pharmacology; Immune response; Immunological memory; Immunotherapy; Intensive; Interferon; Interleukin 10; Interleukin-10 - antagonists & inhibitors; Internal Medicine; KLRG1 protein; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphatic leukemia; Lymphocyte Activation - immunology; Lymphocytes B; Lymphocytes T; Medicine; Medicine & Public Health; Memory cells; Mice; Mice, Inbred NOD; Mice, SCID; Monoclonal antibodies; Oncology; PD-1 protein; PD-L1 protein; Physiological aspects; Plicamycin - pharmacology; Receptor mechanisms; Recovery of function; T cells; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; γ-Interferon; United States
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-021-01217-1

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
32
E
) to suppress CLL IL-10. MTM
ox
32
E
treatment inhibited mouse and human CLL IL-10 production and maintained T-cell effector function in vitro. In the Eμ-Tcl1 mouse model, treatment reduced plasma IL-10 and CLL burden and 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 to anti-PD-L1 alone. Combination therapy also produced more interferon-γ
+
, 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.