CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer.
The participation of a specific subset of B cells and how they are regulated in cancer is unclear. Here, we demonstrate that the proportion of CD5(+) relative to interleukin-6 receptor α (IL-6Rα)-expressing B cells was greatly increased in tumors. CD5(+) B cells responded to IL-6 in the absence of IL-6Rα. IL-6 directly bound to CD5, leading to activation of the transcription factor STAT3 via gp130 and its downstream kinase JAK2. STAT3 upregulated CD5 expression, thereby forming a feed-forward loop in the B cells. In mouse tumor models, CD5(+) but not CD5(-) B cells promoted tumor growth. CD5(+) B cells also showed activation of STAT3 in multiple types of human tumor tissues. Thus, our findings demonstrate a critical role of CD5(+) B cells in promoting cancer.
Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Chunyan
C
Zhang
Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Hong
H
Xin
Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Wang
W
Zhang
Department of Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Paul J
PJ
Yazaki
Department of Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Zhifang
Z
Zhang
Department of Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Keith
K
Le
Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Wenzhao
W
Li
Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Heehyoung
H
Lee
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Larry
L
Kwak
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Stephen
S
Forman
Cell Therapy Institute, Nova Southeastern University, Ft Lauderdale, FL. 33314, USA.
Richard
R
Jove
Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.|Center for Translational Medicine, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, China.
Hua
H
Yu
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D018956:CD5 Antigens / Q000096:biosynthesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D011485:Protein Binding; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology*; D015533:Transcriptional Activation / Q000276:immunology
D018956:CD5 Antigens; C526836:Cd5 protein, mouse; C494200:Il6st protein, mouse; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C113250:interleukin-6 receptor alpha; D050822:Cytokine Receptor gp130; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2