Abstract
Treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has greatly improved clinical outcomes in patients with diffuse large B-cell lymphoma (DLBCL) compared with CHOP. The mechanism of rituximab-induced cell death is poorly understood. We found that rituximab does not enhance the directly killing efficacy of CHOP, as tested on a panel of DLBCL cell lines. Rituximab induced a rapid release of HMGB1 (High mobility group protein B 1). This release is independent of cell death but significantly correlated with an inhibition on STAT3 activity. In the resting state, HMGB1 co-localizes and interacts with STAT3 in the nucleus of DLBCL cells. Treatment with rituximab breaks this binding and triggers HMGB1 release. Treatment with R-CHOP but not CHOP significantly increased plasma HMGB1 and decreased IL-10 concentrations in DLBCL patients compared with controls. The conditioned medium from rituximab-treated DLBCL cells is able to trigger dendritic cell maturation, phagocytosis, and IFN-γ secretion by cytotoxic T cells. In conclusion, our results demonstrate that rituximab induces an inhibition on STAT3 activity, leading to increased HMGB1 release and decreased IL-10 secretion, which elicits immune responses, suggesting that indirect effects on the immune system rather than direct killing contribute to elimination of DLBCL.
Highlights
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most common forms of aggressive and indolent non-Hodgkin lymphomas (NHLs), respectively
We found that rituximab-induced high mobility group protein B1 (HMGB1) release from a panel of DLBCL cell lines is associated with inhibition of STAT3 activity
GA-101, another anti-CD20 antibody, significantly induced cytotoxicity on DLBCL cells but rituximab failed to do so (Figure 1G). These results demonstrate that rituximab may not kill DLBCL cells directly
Summary
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most common forms of aggressive and indolent non-Hodgkin lymphomas (NHLs), respectively. In some of B-cell malignancies, rituximab alone can induce high overall response rates and long term remissions [7, 8]. Previous reports showed that the antiCD20 antibody-treated lymphoma cells are taken up and processed by antigen presenting dendritic cells (DCs) with subsequent cross-presentation of tumor-derived antigens to T cells [15,16,17]. This suggests that anti-CD20 antibodies may have a ‘vaccinal effect’ and exert therapeutic effects through the induction of an adaptive cellular immune response. The precise mechanism by which the anti-CD20 antibody induces immune responses is unclear
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