PT  - JOURNAL ARTICLE
AU  - J.R. Rivas
AU  - S.S. Alhakeem
AU  - Y. Liu
AU  - J.M. Eckenrode
AU  - F. Marti
AU  - J.P. Collard
AU  - Y. Zhang
AU  - K.A. Shaaban
AU  - N. Muthusamy
AU  - G.C. Hildebrandt
AU  - R.A. Fleischman
AU  - L. Chen
AU  - J.S. Thorson
AU  - M. Leggas
AU  - S. Bondada
TI  - Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia
AID  - 10.1101/2020.07.15.204560
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.15.204560
4099  - http://biorxiv.org/content/early/2020/07/17/2020.07.15.204560.short
4100  - http://biorxiv.org/content/early/2020/07/17/2020.07.15.204560.full
AB  - 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, MTMox32E, to suppress CLL IL-10. We found MTMox32E inhibited mouse and human CLL IL-10 production and maintained T-cell 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.Competing Interest StatementJ.S.T. is a co-founder of Centrose (Madision, WI, USA). No other authors have competing financial interests.