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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- Aa:
-
amino acid
- CDR:
-
complementary determining region
- DCIS:
-
ductal carcinoma in situ
- FDC:
-
follicular dendritic cell
- FR:
-
framework region
- IDC:
-
invasive ductal carcinoma
- Ig:
-
immunoglobulin
- MBC:
-
medullary breast carcinoma
- PBMC:
-
peripheral blood mononuclear cell
- TIL-T:
-
tumor-infiltrating T lymphocytes
- TIL-B:
-
tumor-infiltrating B lymphocytes
- VH:
-
Ig heavy chain variable region
References
Hadden JW: The immunology and immunotherapy of breast cancer: an update. Int J Immunopharmacol 21: 79–101, 1999
Ben-Hur H, Cohen O, Schneider D, et al: The role of lymphocytes and macrophages in human breast tumorigenesis: an immunohistochemical and morphometric study. Anticancer Res 22: 1231–1238, 2002
Di Girolamo V, Lauens RP, Coronato S, et al: Quantitative and functional study of breast cancer axillary lymph nodes and those draining other malignant tumors. J Exp Clin Cancer Res 19:155–159, 2000
Allan CP, Turtle CJ, Mainwaring PN, et al: The immune response to breast cancer, and the case for DC immunotherapy. Cytotherapy 6:154–163, 2004
Balch CM, Riley LB, Bae YJ, et al: Patterns of human tumorinfiltrating lymphocytes in 120 human cancers. Arch Surg 125:200–205, 1990
Schwartzentruber DJ, Solomon D, Rosenberg SA, et al: Characterization of lymphocytes infiltrating human breast cancer: specific immune reactivity detected by measuring cytokine secretion. J Immunother 12:1–12, 1992
Lin E, Pollard JW: Role of infiltrated leucocytes in tumour growth and spread. Br J Cancer 90:2053–8, 2004
Ladányi A: Function and prognostic significance of immune cells infiltrating human tumors. (In Hungarian) Magy Onkol 48:49–56, 2004
Filaci G, Fravegy M, Fenoglio D, et al: Non-antigen specific CD8+ T suppressor lymphocytes. Clin Exp Med 4:86–92, 2004
Whitford P, Mallon EA, George WD, et al: Flow cytometric analysis of tumor infiltrating lymphocytes in breast cancer. Br J Cancer 62:971–975, 1990
Lee RS, Schlumberger M, Caillou B, et al: Phenotypic and functional characterisation of tumor-infiltrating lymphocytes. Eur J Cancer 32: 1233–1239, 1996
Chin Y, Janssens J, Bleus J, et al: Characterization of tumor infiltrating lymphocytes in human breast cancer. Eur J Cancer Prev 2 (Suppl. 33): 27–31, 1993
Grekou AN, Toliou T, Stravoravdi P, et al: Correlation of apoptosis with the distribution and composition of lymphocytic infiltrate in human breast carcinomas. Anticancer Res 16:3991–3995, 1996
Ridolfi RL, Rosen PP, Port A, et al: Medullary carcinoma of the breast. A clinicopathology study with 10 year follow-up. Cancer 40:1365–1385, 1977
Coronella JA, Spier C, Welch M, et al: Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast. J Immunol 169:1829–1836, 2002
Nzula S, Going JJ, Stott DI: Antigen driven clonal proliferation, somatic hypermutation, and selection of B lymphocytes infiltrating human ductal breast carcinomas. Cancer Res 63: 3275–3280, 2003
Moore OS, Foote FW: The relatively favourable prognosis of medullary carcinoma of the breast. Cancer 2: 635–640, 1949
Marks JD, Tristem M, Karpas A, et al: Oligonucleotide primers for polymerase chain reaction amplification of human immunoglobulin variable genes and design of family-specific oligonucleotide probes. Eur J Immunol 21:985–991, 1991
Sims GP, Shiono H, Willcox N, et al: Somatic hypermutation and selection of B cells in thymic germinal centers responding to acetylcholine receptor in myasthenia gravis. J Immunol 167:1935–1944, 2001
Tomlinson IM, Williams SC, Ignatovich O, et al: Human VBASE directory of immunoglobulin genes. Cambridge, UK: MRC Centre for Protein Engineering, 1997
Kotlan B, Gruel N, Zafrani B, et al: Immunoglobulin variable regions usage by B-lymphocytes infiltrating a human breast medullary carcinoma. Immunol Lett 65:143–151, 1999
Cuisinier AM, Guigou V, Boubli,et al: Preferential expression of VH5 and VH6 immunoglobulin genes in early human B-cell ontogeny. Scand J Immunol 30: 493–497, 1989
Kotlan B, Simsa P, Foldi J, et al: Immunoglobulin repertoire of B lymphocytes infiltrating breast medullary carcinoma. Human Antibodies 12: 113–121, 2003
Ito T, Saga S, Nagayoshi S, et al: Class distribution of immunoglobulin-containing plasma cells in the stroma of medullary carcinoma of breast. Breast Cancer Res Treat 7:97–103, 1986
Lazzaro B, Anderson AE, Kajdacsy-Balla A, et al: Antigenic characterization of medullary carcinoma of the breast: HLADR expression in lymph node positive cases. Appl Immunohistochem Mol Morphol 9: 234–241, 2001
Gaffey MJ, Frierson HF, Mills SE, et al: Medullary carcinoma of the breast: identification of lymphocyte subpopulations and their significance. Mod Pathol 6:721–728, 1993
Berek C, Berger A, Apel M: Maturation of the immune response in germinal centers. Cell 67:1121–1129, 1991
O’Brien PM, Tsirimonaki E, Coomber DW, et al: Immunoglobulin genes expressed by B-lymphocytes infiltrating cervical carcinomas show evidence of antigen-driven selection. Cancer Immunol Immunother 50:523–532, 2001
Friedman DF, Kraj P, Silberstein LE: VH4.21 Expression in the normal human B-cell repertoire. In: Immunoglobulin Gene Expression in Development and Disease. (Eds: Casali P, Silberstein LE) Ann New York Acad Sc 764:264–274, 1995
Stollar BD: The expressed heavy chain V gene repertoire of circulating B cells in normal adults. In: Immunoglobulin Gene Expression in Development and Disease. (Eds: Casali P, Silberstein LE) Ann New York Acad Sc 764:264–274, 1995
Kotlan B, Simsa P, Teillaud JL et al: Novel ganglioside antigen identified by B cells in human medullary breast carcinomas. The proof of principle concerning the infiltrating B lymphocytes. J Immun, 2005 (in press)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Simsa, P., Teillaud, JL., Stott, D.I. et al. Tumor-infiltrating B cell immunoglobulin variable region gene usage in invasive ductal breast carcinoma. Pathol. Oncol. Res. 11, 92–97 (2005). https://doi.org/10.1007/BF02893374
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02893374