ABSTRACT
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 (MTMox32E) to suppress CLL IL-10. MTMox32E 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.
Subject(s)
B7-H1 Antigen/antagonists & inhibitors , CD8-Positive T-Lymphocytes/immunology , Gene Expression Regulation, Neoplastic/drug effects , Immune Checkpoint Inhibitors/pharmacology , Interleukin-10/antagonists & inhibitors , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Plicamycin/pharmacology , Animals , Antibiotics, Antineoplastic/pharmacology , Apoptosis , CD8-Positive T-Lymphocytes/drug effects , Case-Control Studies , Cell Proliferation , Disease Models, Animal , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Lymphocyte Activation/immunology , Mice , Mice, Inbred NOD , Mice, SCID , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Two cases of intra-articular development of an osteochondroma in the proximal epiphysis of the tibia are reported. The first case, a 3 year old boy, resulted in blocking of the knee. After resection of the mass the diagnosis was confirmed by pathology. The second patient, an 8 year old boy, had no symptoms and surgery was not performed, although ablation was required of an associated astragalian osteochondroma of tibiotarsal intra-articular development. Relations between these epiphyseal osteochondromata and hemimelic epiphyseal dysplasia and metachondromatosis are discussed.
