Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice
Mayuka Horikawa, … , Takashi Matsushita, Thomas F. Tedder
Mayuka Horikawa, … , Takashi Matsushita, Thomas F. Tedder
Published October 24, 2011
Citation Information: J Clin Invest. 2011;121(11):4268-4280. https://doi.org/10.1172/JCI59266.
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Research Article Hematology

Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice

Abstract

Current therapies for non-Hodgkin lymphoma commonly include CD20 mAb to deplete tumor cells. However, the response is not durable in a substantial proportion of patients. Herein, we report our studies in mice testing the hypothesis that heterogeneity in endogenous tissue CD20+ B cell depletion influences in vivo lymphoma therapy. Using highly effective CD20 mAbs that efficiently deplete endogenous mature B cells and homologous CD20+ primary lymphoma cells through monocyte- and antibody-dependent mechanisms, we found that lymphoma depletion and survival were reduced when endogenous host B cells were not depleted, particularly a rare IL-10–producing B cell subset (B10 cells) known to regulate inflammation and autoimmunity. Even small numbers of adoptively transferred B10 cells dramatically suppressed CD20 mAb–mediated lymphoma depletion by inhibiting mAb-mediated monocyte activation and effector function through IL-10–dependent mechanisms. However, the activation of innate effector cells using a TLR3 agonist that did not activate B10 cells overcame the negative regulatory effects of endogenous B10 cells and enhanced lymphoma depletion during CD20 immunotherapy in vivo. Thus, we conclude that endogenous B10 cells are potent negative regulators of innate immunity, with even small numbers of residual B10 cells able to inhibit lymphoma depletion by CD20 mAbs. Consequently, B10 cell removal could provide a way to optimize CD20 mAb–mediated clearance of malignant B cells in patients with non-Hodgkin lymphoma.

Authors

Mayuka Horikawa, Veronique Minard-Colin, Takashi Matsushita, Thomas F. Tedder

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Figure 7

TLR agonists enhance CD20 mAb–induced B cell depletion.

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TLR agonists enhance CD20 mAb–induced B cell depletion. (A) Representati...
(A) Representative TLR-induced TNF-α production by bone marrow CD11b+ cells cultured with brefeldin A for 4 hours. (B) Representative FcγR expression by spleen CD11b+F4/80+ macrophages, Gr-1+ neutrophils, and NK1.1+ NK cells following PBS or TLR agonist treatment. FcγRII/III expression was analyzed by ex vivo immunofluorescence staining 18 hours after the mice were treated. (A and B) Results represent 2 independent experiments. (C) TLR agonists enhance peritoneal cavity B cell depletion by CD20 mAbs. Mice were given CD20 (MB20-11, IgG2c; or MB20-1, IgG1) or isotype control mAbs plus PBS (white circles), poly(I:C) (squares), LPS (black circles), or CpG (triangles). Values represent mean B220+ cell numbers in CD20 versus control mAb-treated mice after 7 days (≥3 mice/value). (D) Peritoneal B1a (CD5+ CD11b+IgMhiB220lo), B1b (CD5–CD11b+IgMhi220lo), and B2 (CD5–CD11b–IgMhiB220hi) cell numbers in mice 7 days after CD20 (MB20-11, black bars) or control (white bars) mAb (25 μg) treatment plus PBS, poly(I:C), LPS, or CpG (≥3 mice per value). (E) CpG does not augment peritoneal cavity B cell depletion by CD20 mAbs (MB20-11, 25 μg) in Myd88–/– mice. Percentages represent mean B220+ cell frequencies 7 days after CD20 mAb treatment relative to control mAb-treated littermates (≥3 mice per value). CD19+ B cells from WT and Myd88–/– mice express similar cell-surface CD20 densities as assessed over a range of CD20 mAb concentrations relative to control mAbs (10 μg/ml) binding. (C–E) Significant differences between sample means are indicated. *P < 0.05; **P < 0.01. Results represent 3–4 independent experiments. Data represent mean ± SEM.