The Shaping of a Polyvalent and Highly Individual T-Cell Repertoire in the Bone Marrow of Breast Cancer Patients

Nora Sommerfeldt,Philipp Beckhove,Volker Schirrmacher,Florian SchüTz,Joanna FöRster,Christoph Sohn

doi:10.1158/0008-5472.can-05-4201

Nora Sommerfeldt, Philipp Beckhove + Show 4 more

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https://doi.org/10.1158/0008-5472.can-05-4201

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Abstract

We analyzed the T-cell repertoires from the bone marrow of 39 primary operated breast cancer patients and 11 healthy female donors for the presence and frequencies of spontaneously induced effector/memory T lymphocytes with peptide-HLA-A2-restricted reactivity against 10 breast tumor-associated antigens (TAA) and 3 normal breast tissue-associated antigens by short-term IFN-gamma enzyme-linked immunospot (ELISpot) analysis. Sixty-seven percent of the patients recognized TAAs with a mean frequency of 144 TAA reactive cells per 10(6) T cells. These patients recognized simultaneously an average of 47% of the tested TAAs. The T-cell repertoire was highly polyvalent and exhibited pronounced interindividual differences in the pattern of TAAs recognized by each patient. Strong differences of reactivity were noticed between TAAs, ranging from 100% recognition of prostate-specific antigen(p141-149) to only 25% recognition of MUC1(p12-20) or Her-2/neu(p369-377). In comparison with TAAs, reactivity to normal breast tissue-associated antigens was lower with respect to the proportions of responding patients (30%) and recognized antigens (27%), with a mean frequency of only 85/10(6) T cells. Healthy individuals also contained TAA-reactive T cells but this repertoire was more restricted and the frequencies were in the same range as T cells reacting to normal breast tissue-associated antigens. Our data show a highly individual T-cell repertoire for recognition of TAAs in breast cancer patients. This has potential relevance for T-cell immune diagnostics, for tumor vaccine design, and for predicting immune responsiveness.

Highlights

During the last years, evidence has increased that malignant human tumors can be naturally recognized by the host’s immune system and induce spontaneous tumor antigen–specific T-cell responses, which together constitute an antitumoral T-cell memory repertoire in lymphoid tissues, such as the bone marrow [1,2,3,4,5]
We describe the results of short-term IFN-g enzyme-linked immunospot (ELISpot) analyses with ex vivo isolated bone marrow T cells from 39 primary operated breast cancer patients and 11 healthy female donors tested for the presence and frequencies of spontaneously induced effector/memory T lymphocytes with reactivity against altogether 17 defined, HLA-A2-restricted nonameric peptides derived from 10 different tumor-associated antigens (TAA) and 3 non-malignancyassociated antigens
17 wellcharacterized, HLA-A2-restricted nonapeptides were selected for detection of antigen-reactive T cells (Tables 1 and 2)

Summary

Introduction

Evidence has increased that malignant human tumors can be naturally recognized by the host’s immune system and induce spontaneous tumor antigen–specific T-cell responses, which together constitute an antitumoral T-cell memory repertoire in lymphoid tissues, such as the bone marrow [1,2,3,4,5]. We decided to analyze the T-cell repertoire of breast cancer patients because breast cancer is among the most frequent tumors worldwide and a leading cause of death in women. We focused this analysis on the bone marrow as a T-cell source because many attempts to detect functional tumor-reactive T cells in the blood of tumor patients have failed [1,2,3, 12, 13]. Recent studies showed high frequencies of TAA-specific memory T cells in the bone marrow of patients with multiple myeloma, pancreatic carcinoma, and breast cancer, whereas they showed no TAAspecific immunoreactivity in their peripheral blood [1, 3, 4]

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