Chronic lymphocytic leukemia-derived IL-10 suppresses antitumor immunity

Sara S. Alhakeem, Mary K. McKenna, Karine Z. Oben, Sunil K. Noothi, Jacqueline R. Rivas, Gerhard C. Hildebrandt, Roger A. Fleischman, Vivek M. Rangnekar, Natarajan Muthusamy, Subbarao Bondada

Research output: Contribution to journalArticlepeer-review

42 Citations (SciVal)

Abstract

Chronic lymphocytic leukemia (CLL) patients progressively develop an immunosuppressive state. CLL patients have more plasma IL-10, an anti-inflammatory cytokine, than healthy controls. In vitro human CLL cells produce IL-10 in response to BCR crosslinking. We used the transgenic Eμ-T cell leukemia oncogene-1 (TCL1) mouse CLL model to study the role of IL-10 in CLL associated immunosuppression. Eμ-TCL mice spontaneously develop CLL because of a B cell-specific expression of the oncogene, TCL1. Eμ-TCL1 mouse CLL cells constitutively produce IL-10, which is further enhanced by BCR cross-linking, CLL-derived IL-10 did not directly affect survival of murine or human CLL cells in vitro.We tested the hypothesis that the CLL-derived IL-10 has a critical role in CLL disease in part by suppressing the host immune response to the CLL cells. In IL-10R -/- mice, wherein the host immune cells are unresponsive to IL-10-mediated suppressive effects, there was a significant reduction in CLL cell growth compared with wild type mice. IL-10 reduced the generation of effector CD4 and CD8 T cells. We also found that activation of BCR signaling regulated the production of IL-10 by both murine and human CLL cells. We identified the transcription factor, Sp1, as a novel regulator of IL-10 production by CLL cells and that it is regulated by BCR signaling via the Syk/MAPK pathway. Our results suggest that incorporation of IL-10 blocking agents may enhance current therapeutic regimens for CLL by potentiating host antitumor immune response.

Original languageEnglish
Pages (from-to)4180-4189
Number of pages10
JournalJournal of Immunology
Volume200
Issue number12
DOIs
StatePublished - Jun 15 2018

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grant CA 165469, the Flow Cytometry and Biospecimen Procurement and Translational Pathology shared resource facilities of the Markey Cancer Center (Grant P30CA177558), and Alzheimer’s Disease Center Grant P30-AG028383 at the University of Kentucky.

Publisher Copyright:
Copyright © 2018 by The American Association of Immunologists, Inc.

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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