title: Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4⁺ T cells to T-regulatory cells.
abstract: Pulmonary metastasis of breast cancer requires recruitment and expansion of T-regulatory cells (Treg) that promote escape from host protective immune cells. However, it remains unclear precisely how tumors recruit Tregs to support metastatic growth. Here we report the mechanistic involvement of a unique and previously undescribed subset of regulatory B cells. These cells, designated tumor-evoked Bregs (tBreg), phenotypically resemble activated but poorly proliferative mature B2 cells (CD19(+) CD25(High) CD69(High)) that express constitutively active Stat3 and B7-H1(High) CD81(High) CD86(High) CD62L(Low) IgM(Int). Our studies with the mouse 4T1 model of breast cancer indicate that the primary role of tBregs in lung metastases is to induce TGF-β-dependent conversion of FoxP3(+) Tregs from resting CD4(+) T cells. In the absence of tBregs, 4T1 tumors cannot metastasize into the lungs efficiently due to poor Treg conversion. Our findings have important clinical implications, as they suggest that tBregs must be controlled to interrupt the initiation of a key cancer-induced immunosuppressive event that is critical to support cancer metastasis.
authors: Immunotherapeutics Unit, Laboratory of Immunology, National Institute on Aging, Baltimore, Maryland 21224, USA.
authors: Purevdorj B
authors: PB
authors: Olkhanud
authors: Bazarragchaa
authors: B
authors: Damdinsuren
authors: Monica
authors: M
authors: Bodogai
authors: Ronald E
authors: RE
authors: Gress
authors: Ranjan
authors: R
authors: Sen
authors: Katarzyna
authors: K
authors: Wejksza
authors: Enkhzol
authors: E
authors: Malchinkhuu
authors: Robert P
authors: RP
authors: Wersto
authors: Arya
authors: A
authors: Biragyn
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors