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

Non-Hodgkin’s lymphoma (NHL) is a heterogeneous group of malignancies that represents ~4% of all cancers. Rituximab, a chimeric CD20 monoclonal antibody (mAb) that effectively treats half of NHL patients variably depletes non-malignant tissue B cells. Whether endogenous or remnant B cells affect CD20 mAb-induced lymphoma depletion is unknown. To determine whether endogenous B cells can influence in vivo lymphoma therapy in mice, the therapeutic effectiveness of a potent mouse anti-mouse CD20 mAb was compared in wild type and CD20-deficient (CD20-/-) mice given homologous CD20+ primary lymphoma cells. CD20 mAb efficiently depleted endogenous mature B cells and lymphoma cells in wild type mice and prolonged survival significantly. By contrast, endogenous B cells are not depleted in CD20-/- mice, including a rare IL-10-producing regulatory B cell subset (B10 cells). Furthermore, the persistence of endogenous B cells significantly inhibited the anti-tumor effects of CD20 mAb in CD20-/- mice. Even small numbers of adoptively transferred CD20-/- B10 cells dramatically suppressed lymphoma depletion in wild type mice by inhibiting monocyte activation and effector function through IL-10-dependent mechanisms. Thus, endogenous B10 cells are potent negative regulators of innate immunity, with even small numbers of residual B10 cells inhibiting lymphoma depletion by CD20 mAb. This may provide a new explanation for treatment resistance in some lymphoma patients.