Antigen-driven clonal proliferation, somatic hypermutation, and selection of B lymphocytes infiltrating human ductal breast carcinomas.
Infiltration of B lymphocytes into the tumor tissue of breast cancer patients is a common occurrence, but the role of these cells in the immune response to the tumor is unknown. Heavy B-cell infiltration in medullary breast carcinoma is well documented and associated with a more favorable prognosis, implying a positive role for the humoral immune response in elimination of tumor cells. Variable B-cell infiltration has also been detected in infiltrating ductal carcinomas of the breast, but little is known about the immunoglobulin gene repertoire of these tumor-infiltrating B lymphocytes and whether they are actively responding to a local stimulus or merely passive bystanders. We have therefore investigated the repertoire of B cells infiltrating four invasive ductal carcinomas. A group of 233 rearranged Ig V(H) genes was amplified, cloned, and sequenced from microdissected foci of infiltrating B cells. B cells within individual foci were polyclonal, and most were highly mutated. Several foci expressed dominant sets of V genes derived from B-cell clones. Some of these were found in more than one lymphoid cluster, indicating that B cells had migrated into the surrounding tissue and seeded new clusters. Analysis of the pattern of mutations in clonally related sets of Ig V genes expressed by tumor-infiltrating B cells shows that these cells are undergoing antigen-driven proliferation, somatic hypermutation, and affinity maturation in situ.
Nzula
Sazini
S
Division of Immunology, Infection and Inflammation, University of Glasgow, Western Infirmary, Glasgow, G11 6NT, Scotland, United Kingdom. sn34y@clinmed.gla.ac.uk
Going
James J
JJ
Stott
David I
DI
D000915:Antibody Affinity; D000951:Antigens, Neoplasm / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000276:immunology* / Q000473:pathology; D002455:Cell Division; D002465:Cell Movement; D002999:Clone Cells / Q000276:immunology; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D017422:Sequence Analysis, DNA; D027041:Somatic Hypermutation, Immunoglobulin
D000951:Antigens, Neoplasm; D007135:Immunoglobulin Variable Region