Tumor-infiltrating B cell immunoglobulin variable region gene usage in invasive ductal breast carcinoma

Abstract

A major focus of tumor immunology is to reveal the potential role and capacity of immunocompetent cells found in different solid tumor tissues. The most abundant infiltrating cells (TIL), the T lymphocytes have been investigated in details concerning T-cell receptor usage and specificity. However, B cells have hardly been investigated in this respect, although high cellular B-cell infiltration has been correlated with improved patients' survival in some breast carcinomas. This led to our objectives to study variable region gene usage of the tumor-infiltrating B cells in different breast carcinoma types. By defining the immunoglobulin repertoire of the tumor-infiltrating B lymphocytes in the most common invasive ductal carcinoma (IDC) of the breast we compared it to the rare medullary breast carcinoma (MBC). After phenotyping infiltrating ductal carcinomas, B cells were obtained from tumor tissue by microdissection technique. Numerous rearranged TIL-B immunoglobulin heavy chain V genes (VH) were amplified, cloned, sequenced, and comparatively analyzed. Some characteristics were found for both breast carcinoma types. The immunoglobulins produced by TIL-B in ductal carcinoma are highly matured and oligoclonal. We conclude that Ig variable region gene usage reveals similar and distinguishable characteristics of TIL-B immunoglobulin repertoires, which are representative of the nature of the immune responses in invasive ductal and medullary breast carcinomas.

Focused antibody response in plasma cell-infiltrated non-medullary (NOS) breast cancers

“…(No report assayed VL usage.) Two studies performed microdissection of a small number of B cell follicles identified in tumors that also included limited numbers of PCs, cloning VH with class-independent primers that do not reveal Ig type [37,38]. As noted above, normal breast epithelium and breast cancers with small-to-moderate PC reaction are typically dominated by IgA PCs [28].…”

CD20+ B Cells: The Other Tumor-Infiltrating Lymphocytes

“…TIL-Bs appear early during breast tumorigenesis, being present at the ductal carcinoma in situ stage (49). TIL-Bs generally express IgG and show evidence of Ag-driven expansion and somatic mutation consistent with affinity maturation (50)(51)(52)(53)(54)(55). In one IgG sequencing study, .45% of TIL-B belonged to a clonal group, and there were 4-11 major clonal groups per tumor (46).…”

The Immune Microenvironment of Human Tumors: General Significance and Clinical Impact

“…These dual effects may be due to the tumor cells and/or the inflammatory context. The case of B lymphocytes is also unclear: they correlate with tumor growth and invasion in murine models [44][45][46][47] but scarce observations associate a B cells signature to good prognosis in several human cancers [48][49][50]. Intratumoral NK cells have been reported to down regulate their activating receptors and to be associated to larger breast [51] and lung [28] tumors, but without clear impact on patients survival.…”