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Antigen-driven Clonal Proliferation, Somatic Hypermutation, and Selection of B Lymphocytes Infiltrating Human Ductal Breast Carcinomas¹

Division of Immunology, Infection and Inflammation, and Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Western Infirmary, Glasgow, G11 6NT, Scotland, United Kingdom

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.

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