Format

Send to

Choose Destination
Oncotarget. 2015 Sep 29;6(29):27816-31. doi: 10.18632/oncotarget.4816.

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

Author information

1
Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
2
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
3
Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
4
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

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.

KEYWORDS:

DLBCL; HMGB1; STAT3; immunogenic cell death; rituximab

PMID:
26315113
PMCID:
PMC4695028
DOI:
10.18632/oncotarget.4816
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center