Oncotarget

Research Papers:

Rituximab-induced HMGB1 release is associated with inhibition of STAT3 activity in human diffuse large B-cell lymphoma

Tiansuo Zhao, He Ren, Xiuchao Wang, Pengfei Liu, Fan Yan, Wenna Jiang, Yang Li, Jing Li, John G Gribben, Li Jia and Jihui Hao _

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Oncotarget. 2015; 6:27816-27831. https://doi.org/10.18632/oncotarget.4816

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Abstract

Tiansuo Zhao1, He Ren1, Xiuchao Wang1, Pengfei Liu2, Fan Yan3, Wenna Jiang1, Yang Li1, Jing Li1, John G. Gribben4, Li Jia4, Jihui Hao1

1Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China

2Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China

3Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China

4Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK

Correspondence to:

Jihui Hao, e-mail: haojihui@tjmuch.com

Li Jia, e-mail: L.jia@qmul.ac.uk

Keywords: DLBCL, rituximab, immunogenic cell death, HMGB1, STAT3

Received: July 01, 2015     Accepted: July 20, 2015     Published: July 31, 2015

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.


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