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Evaluation of Pre-existent Immunity in Patients with Primary Breast Cancer

Molecular and Cellular Assays to Quantify Antigen-Specific T Lymphocytes in Peripheral Blood Mononuclear Cells

Department of Obstetrics and Gynecology [C. R., S. K., I. W., D. W., B. G.] and Department of Immunology, Institute for Cell Biology [S. W., S. Ste.], University of Tübingen, 72076 Tübingen, Germany, and Institute of Immunology, University of Heidelberg, Heidelberg, Germany [S. Stu.]

Purpose: Breast cancers are known to frequently (over)express several well-characterized tumor-associated antigens (TAAs) such as carcinoembryonic antigen, MUC-1, Her-2/neu, and cancer/testis antigens such as NY-ESO-1, SSX-2, and members of the MAGE family. Whereas in melanoma patients, the detection of pre-existing T cell responses to tumor-associated differentiation antigens was a rationale to initiate several vaccination strategies, little is known thus far concerning tumor-specific immunity in breast cancer patients. The objectives of our study were (a) to modify and compare different immunodiagnostic T cell assays with regard to their suitability for clinical applications and (b) to determine endogenous TAA-specific T cell immunity of breast cancer patients at the time point of primary diagnosis.

Experimental Design: Using MUC-1- and Her-2/neu-derived HLA-A*0201-restricted peptides as model antigens, we analyzed antigen-dependent IFN- release of T cells by enzyme-linked immunospot (ELISpot) assay, intracellular cytokine flow cytometry (CytoSpot), and quantitative real-time PCR. As an assay independent of T cell function, we performed tetramer staining.

Results: In our hands, the quantitative real-time PCR method is most sensitive and a feasible screening test to perform an "immunological staging" of cancer patients. By doing this, we detected in 7 of 13 (54%) of HLA-A*0201⁺ breast cancer patients a pre-existent specific cellular immune response to at least one of the investigated TAAs (MUC-1, Her-2/neu, carcinoembryonic antigen, NY-ESO-1, and SSX-2). Four of 21 patients (19%) were found to have a significant Her-2/neu-specific T cell response as defined by a stimulation index 2 (range, 10–88).

Conclusions: Although the clinical relevance of endogenous TAA-specific immunity remains unclear, our findings suggest that patients with primary breast cancer can mount a T cell immune response to their tumor that might be beneficially enhanced by TAA-dependent vaccination strategies in the adjuvant situation.

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