title: Rituximab-induced HMGB1 release is associated with inhibition of STAT3 activity in human diffuse large B-cell lymphoma.
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.
authors: Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
authors: Tiansuo
authors: T
authors: Zhao
authors: Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
authors: He
authors: H
authors: Ren
authors: Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
authors: Xiuchao
authors: X
authors: Wang
authors: Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
authors: Pengfei
authors: P
authors: Liu
authors: Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
authors: Fan
authors: F
authors: Yan
authors: Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
authors: Wenna
authors: W
authors: Jiang
authors: Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
authors: Yang
authors: Y
authors: Li
authors: Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
authors: Jing
authors: J
authors: Li
authors: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors: John G
authors: JG
authors: Gribben
authors: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors: Li
authors: L
authors: Jia
authors: Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
authors: Jihui
authors: J
authors: Hao
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003520:Cyclophosphamide; D004317:Doxorubicin; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000276:immunology / Q000378:metabolism*; D011241:Prednisone; D000069283:Rituximab / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014750:Vincristine
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C571759:R-CHOP protocol; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone
keywords: DLBCL; HMGB1; STAT3; immunogenic cell death; rituximab