Tumor-released autophagosomes induce IL-10-producing B cells with suppressive activity on T lymphocytes via TLR2-MyD88-NF-κB signal pathway.
Recent studies have shown that tumor cells can release autophagosomes, which transport a broad array of biologically active molecules with potential modulatory effects on immune cell functions. In this study, we aimed to investigate the role of tumor cells-released autophagosomes (i.e. TRAP) in regulating B cell differentiation and function. TRAPs from murine tumor cell lines were found to induce splenic B cells to differentiate into IL-10-producing regulatory B cells (Bregs) with a distinct phenotype of CD1d(+) CD5(+), which could potently inhibit CD8(+) and CD4(+) T cell responses in IL-10-depedent manner both in vitro and in vivo. Notably, adoptive transfer of TRAP-induced Bregs abrogated the immune response and antitumor effect induced by OVA-loaded DC vaccinations in E.G7-OVA-bearing mouse model. Mechanistic studies revealed that membrane-bound high-mobility group B1 (HMGB1) on the intact TRAPs was crucial for inducing Breg differentiation via the activation of TLR2-MyD88-NF-κB signal pathway in B cells. Moreover, TRAPs enriched from malignant effusions of cancer patients could induce human B cells to differentiate into IL-10-producing B cells with immunoregulatory functions, the frequency of which were positively correlated with the HMGB1 levels on TRAPs. Together, our findings have demonstrated that TRAPs promote the generation of IL-10(+) Bregs, which may contribute to the suppression of antitumor immunity.
Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China.
Meng
M
Zhou
Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China.
Zhifa
Z
Wen
Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China.
Feng
F
Cheng
Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China.
Jie
J
Ma
Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China.
Weixia
W
Li
Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China.
Hongyan
H
Ren
Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China.
Yemeng
Y
Sheng
Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China.
Huixia
H
Dong
Department of Pathology and Center of Infection and Immunology, The University of Hong Kong , Hong Kong, Special Administrative Region, P.R. China.
Liwei
L
Lu
Laboratory of Cancer Immunobiology, Earle A. Chiles Research Institute, Providence Portland Medical Center , Portland, OR, USA.
Hong-Ming
HM
Hu
Department of Microbiology and Immunology, Medical School of Southeast University , Nanjing, Jiangsu Province, P.R. China.
Li-Xin
LX
Wang
HMGB1; IL-10; TLR2; regulatory B cells; tumor-released autophagosomes (TRAP)