title: Mammary-tumor-educated B cells acquire LAP/TGF-β and PD-L1 expression and suppress anti-tumor immune responses.
abstract: B lymphocytes play a role in inhibiting the immune response against certain tumors, but the underlying mechanisms are poorly understood. EMT-6 mammary tumors grow well in wild-type (WT) mice but show reduced growth in B-cell-deficient μ(-/-) BALB/c mice (BCDM). WT mice demonstrate extensive B-cell infiltration into the tumor bed, reduced CD8(+) T cell and CD49(+) NK cell infiltration, and markedly reduced cytolytic T-cell response relative to BCDM. Expression of LAP/TGF-β1, CD80, CD86 and PD-L1 is significantly increased in tumor-infiltrating B cells (TIL-B) relative to splenic B cells. LAP/TGF-β1 expression on TIL-B progressively increased from 5.4±1.7% on day 8 to 43.1±6.1% by day 21 post tumor implantation. Co-culture of EMT-6 tumor cells with Naive-B cells ex vivo generated B cells (EMT6-B) with a similar immunophenotype to TIL-B. Purified TIL-B, or in-vitro-generated EMT6-B suppressed CD4(+), CD8(+) and CD4(+)CD25(-) T-cell proliferation, and Th1 cytokine secretion, and also suppressed purified NK-cell proliferation in response to IL-15, compared to naive splenic B cells. Acquired B regulatory function required direct tumor cell: B-cell contact, and was partially reversed by antibody to TGF-β or PD-L1, leading to tumor rejection in vivo B-cell acquisition of a suppressive phenotype following tumor infiltration may result in profound inhibition of T-cell anti-tumor responses.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA y.zhang4@med.miami.edu.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Morgan
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: Chen
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
authors.forename: Yancheng
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Clark
authors.affiliation: Department of Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Wasif Noor
authors.initials: WN
authors.lastname: Khan
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
authors.forename: Seung-Uon
authors.initials: SU
authors.lastname: Shin
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
authors.forename: Hyun-Mi
authors.initials: HM
authors.lastname: Cho
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al Bayati
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
authors.forename: Augustin
authors.initials: A
authors.lastname: Pimentel
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Rosenblatt
mesh_terms: D000818:Animals; D060151:B-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C497965:Cd86 protein, mouse; D009363:Neoplasm Proteins; D016212:Transforming Growth Factor beta
keywords: B regulatory cells; PD-L1; TGF-β; anti-tumor response