Format

Send to

Choose Destination
J Immunol. 2018 Jun 15;200(12):4180-4189. doi: 10.4049/jimmunol.1800241. Epub 2018 Apr 30.

Chronic Lymphocytic Leukemia-Derived IL-10 Suppresses Antitumor Immunity.

Author information

1
Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536.
2
Markey Cancer Center, University of Kentucky, Lexington, KY 40536.
3
Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536.
4
Division of Hematology, Blood, and Marrow Transplantation, University of Kentucky, Lexington, KY 40536.
5
Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; and.
6
Department of Internal Medicine, The Ohio State University, Columbus, OH 43210.
7
Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536; bondada@email.uky.edu.

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 cross-linking. 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.

PMID:
29712773
DOI:
10.4049/jimmunol.1800241
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center