title: Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast.
abstract: The objective of this study was to determine whether tumor-infiltrating B cells (TIL-B) of infiltrating ductal carcinoma (IDC) of the breast represent a tumor-specific humoral immune response. Immunohistochemical analysis of three Her-2/neu-negative IDC tumors from geriatric patients showed that TIL-B cluster in structures similar to germinal centers containing CD20(+) B lymphocyte and CD3(+) T lymphocyte zones with interdigitating CD21(+) follicular dendritic cells, suggesting an in situ immune response. A total of 29, 31, and 58 IgG1 H chain clones was sequenced from the three IDC tumors, respectively. Intratumoral oligoclonal expansion of TIL-B was demonstrated by a preponderance (45-68%) of clonal B cells. In contrast, only 7% of tumor-draining lymph node and 0% of healthy donor PBL IgG H chains were clonal, consistent with the larger repertoires of node and peripheral populations. Patterns and levels of TIL-B IgG H chain somatic hypermutation suggested affinity maturation in intratumoral germinal centers. To examine the specificity of TIL-B Ig, a phage-displayed Fab library was generated from the TIL-B of one IDC tumor. Panning with an allogeneic breast cancer cell line enriched Fab binding to breast cancer cells, but not nonmalignant cell lines tested. However, panning with autologous tumor tissue lysate increased binding of Fab to both tumor tissue lysate and healthy breast tissue lysate. These data suggest an in situ Ag-driven oligoclonal B cell response to a variety of tumor- and breast-associated Ags.
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA. jcoronella@azcc.arizona.edu
authors.forename: Julia A
authors.initials: JA
authors.lastname: Coronella
authors.forename: Catherine
authors.initials: C
authors.lastname: Spier
authors.forename: Matthew
authors.initials: M
authors.lastname: Welch
authors.forename: Katrina T
authors.initials: KT
authors.lastname: Trevor
authors.forename: Alison T
authors.initials: AT
authors.lastname: Stopeck
authors.forename: Hugo
authors.initials: H
authors.lastname: Villar
authors.forename: Evan M
authors.initials: EM
authors.lastname: Hersh
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000276:immunology* / Q000473:pathology; D005260:Female; D005803:Genes, Immunoglobulin; D018858:Germinal Center / Q000276:immunology / Q000473:pathology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D009154:Mutation; D019151:Peptide Library; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D007140:Immunoglobulin Fab Fragments; D019151:Peptide Library