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Novel Ganglioside Antigen Identified by B Cells in Human Medullary Breast Carcinomas: The Proof of Principle Concerning the Tumor-Infiltrating B Lymphocytes¹

Beatrix Kotlan^*,,¶, Peter Simsa^*, Jean-Luc Teillaud, Wolf Herman Fridman, Jozsef Toth, Michael McKnight^,¶ and Mark C. Glassy^2,,¶,||

^* National Medical Center/Institute of Haematology and Immunology, Budapest, Hungary; Institut National de la Santé et de la Recherche Médicale Unité 255, Centre de Recherches Biomedicales des Cordeliers, Universite Pierre et Marie Curie, Paris, France; National Institute of Oncology, Budapest, Hungary; Rajko Medenica Research Foundation, San Diego, CA 92121; ^¶ Shantha West, San Diego, CA 92121; and ^|| University of California, San Diego Mechanical and Aerospace Engineering Department, La Jolla, CA 92037

The potential tumor-recognizing capacity of B cells infiltrating human breast carcinoma is an important aspect of breast cancer biology. As an experimental system, we used human medullary breast carcinoma because of its heavy B lymphocytic infiltration paralleled to a relatively better prognosis. Ig-rearranged V region V_H-J_H, V-J, and V-J genes, amplified by RT-PCR of the infiltrating B cells, were cloned, sequenced, and subjected to a comparative DNA analysis. A combinatorial single-chain variable fragment Ab minilibrary was constructed out of randomly selected V_H and V clones and tested for binding activity. Our data analysis revealed that some of the V_H-J_H, V-J, and V-J region sequences were being assigned to clusters with oligoclonal predominance, while other characteristics of the Ab repertoire were defined also. A tumor-restricted binder clone could be selected out of the single-chain variable fragment minilibrary tested against membrane fractions of primary breast tumor cells and tumor cell lines, the V_H of which proved to be the overexpressed V_H3-1 cluster. The specific binding was confirmed by FACS analysis with primary breast carcinoma cells and MDA-MB 231 cell line. ELISA and thin layer chromatography dot-blot experiments showed this target Ag to be a ganglioside D3 (GD3). Our results are a proof of principle about the capacity of B cells infiltrating breast carcinomas to reveal key cancer-related Ags, such as the GD3. GD3-specific Abs may influence tumor cell progression and could be used for further development of diagnostic and/or therapeutic purposes.

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