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IMMUNOTHERAPY

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

Leukemia volume 35, pages 3188–3200 (2021)Cite this article

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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.

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Fig. 1: CLL IL-10 suppresses T-cell responses.
Fig. 2: MTMox32E suppresses CLL IL-10 without dampening in vitro T-cell responses.
Fig. 3: MTMox32E enhances anti-CLL activity of CD8+ T-cells and suppresses CLL IL-10 production in vivo.
Fig. 4: Inhibiting CLL IL-10 with MTMox32E increases the numbers of T- effector cells.
Fig. 5: Anti-PD-L1 checkpoint blockade is more effective when combined with IL-10 suppression by MTMox32E.
Fig. 6: T-cells from Eμ-TCL1 mice are more functional when treated with both anti-PD-L1 checkpoint blockade and IL-10 blockade.
Fig. 7: Cooperation of IL-10 suppression and immune checkpoint blockade.

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Acknowledgements

We would like to thank the patients and their families for participating in our research and Dr Siva Gandhapudi and Dylan Rivas for their helpful discussion. Jacqueline R. Rivas is a Fellow of the Leukemia & Lymphoma Society and was partially supported by the NCI Training Grant T32CA165990. This project was supported in part by R01CA165469 (SB), R01CA217934 (SB), R01CA217255 (JST), and R01GM115261 (JST). We also acknowledge the support from the National Center for Advancing Translational Sciences (UL1TR001998 and UL1TR000117), the Center of Biomedical Research Excellence (COBRE) in Pharmaceutical Research and Innovation (CPRI, P20GM130456), the University of Kentucky College of Pharmacy PharmNMR Center, the University of Kentucky Markey Cancer Center and Markey Cancer Center’s Flow Cytometry and Immune Monitoring Shared Resource Facility (P30CA177558). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, USA

    J. R. Rivas, S. S. Alhakeem, J. P. Collard, G. C. Hildebrandt & S. Bondada

  2. Markey Cancer Center, University of Kentucky, Lexington, KY, USA

    J. R. Rivas, S. S. Alhakeem, J. P. Collard, G. C. Hildebrandt, R. A. Fleischman, L. Chen, J. S. Thorson, M. Leggas & S. Bondada

  3. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA

    Y. Liu, J. M. Eckenrode, Y. Zhang, K. A. Shaaban, J. S. Thorson & M. Leggas

  4. Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY, USA

    Y. Liu, Y. Zhang, K. A. Shaaban, J. S. Thorson & M. Leggas

  5. Department of Surgery, University of Kentucky, Lexington, KY, USA

    F. Marti

  6. Department of Internal Medicine and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA

    N. Muthusamy

  7. Division of Hematology and Blood and Marrow Transplant, University of Kentucky, Lexington, KY, USA

    G. C. Hildebrandt & R. A. Fleischman

  8. Department of Biostatistics, University of Kentucky, Lexington, KY, USA

    L. Chen

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Rivas, J.R., Liu, Y., Alhakeem, S.S. et al. Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia. Leukemia 35, 3188–3200 (2021). https://doi.org/10.1038/s41375-021-01217-1

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