Targets of B Cell Infiltrate in Medullary Breast Cancer

Institution: Scripps Research Institute
Investigator(s): Henrik Ditzel, M.D., Ph.D -
Award Cycle: 1998 (Cycle IV) Grant #: 4JB-0019 Award: $279,890
Award Type: IDEAS II
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1998)
Medullary breast cancer, a subtype of human breast cancers that is characterized by white blood cell infiltrates in the tumor periphery, has been found to have a favorable prognosis as compared to other types of breast cancers at a similar disease stage. The presence of these white blood cells in the tumor has been suggested as a reason for the better prognosis. It is thus of great interest to identify the target of these white cells since this may have important implications for detection and treatment, not only for medullary breast cancers, but breast cancers in general. Previous studies indicate that the T white blood cells are not driving the immune response. The essence of the project is to evaluate the role of the B white blood cell infiltrates in medullary breast cancer. The proposal takes advantage of recently developed molecular techniques for the production of human monoclonal antibodies, which are secreted by the white cells, and identification of the target of these antibodies (the antigens). Preliminary results indicate that a few antibodies dominate the tumor-infiltrating B white blood cell response.

There are several goals for this study. The first is to identify human antibodies in the tumor-infiltrate of medullary breast cancer capable of binding to the cancer cells. The second is to characterize these antibodies by different techniques. The third is to identify the breast cancer component that is the target of these antibodies (by cDNA cloning) and determine where it is located in the cell and throughout the body. It is hoped that the results from this study will influence how breast cancer tumor vaccines are designed.

Final Report (2000)
Medullary carcinoma of the breast (MCB) is a distinct subtype of human breast cancer that has a better prognosis than other types of breast cancer. It has been proposed that the improved clinical outcome is due, at least in part, to the presence of a prominent white blood infiltrate in the tumor tissue. We studied the B cells of the white blood cell infiltrates in MCB to determine the role of the antibody response produced by these infiltrating cells.

A limited amount of tumor infiltrating B white blood cells dominated the response in a panel of MC13 patients, suggesting that these B cell clones were expanded, possibly in response to specific tumor associated stimuli. Antibody phage display libraries were generated from MCB infiltrating labile blood cells of two patients and MCB reactive monoclonal antibodies retrieved by selection on MCB tissue sections. The target protein of the selected antibodies was studied and purified from MCB lysate. Analysis revealed that the protein targeted by the dominant clones in the B white blood response in both patients was not a cancer specific antigen but the structural protein actin. MCB exhibits an increased rate of cell death and MCB cells undergoing cell death were shown to have actin on the cell surface, permitting its recognition by the immune system. Further, actin pieces, similar to those observed after cleavage with the cell death enzymes granzyme B, were observed in MCB tissue.

Our results indicate that the antibody response produced by tumor infiltradog B white blood cells are autoimmune in nature and a consequence of the disease state of increased MCB cell death caused by enzymes found in T white blood cells and/or internal cellular factors of MCB cells.

The tumor-infiltrating B cell response in medullary breast cancer is oligoclonal and directed against the autoantigen actin exposed on the surface of apoptotic cancer cells
Periodical:Proceedings of the National Academy of Sciences of the United States of America
Index Medicus: Proc Nat Acad Sci, U S A
Authors: Hansen MH, Nielsen H, Ditzel HJ
Yr: 2001 Vol: 98 Nbr: 22 Abs: Pg:12659-64

Human antibodies in cancer and autoimune disease
Periodical:Immunologic Research
Index Medicus: Immunol Res
Authors: Ditzel, H.J.
Yr: 2000 Vol: 21 Nbr: 2-3 Abs: Pg:185-93