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

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 tumorassociated antigens (TAA) and 3 normal breast tissueassociated antigens by short-term IFN-; 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. (Cancer Res 2006; 66(16): 8258-65)

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

“…In line with our previous findings 23,24,26 , we detected both wt and mutated peptide-specific memory T cell responses that were polyvalent in the majority of patients. The responses against mutated peptides were overall higher than those against wt peptides arguing for mutation specificity of the tumor Ag specific T cell pool in CRC patients and for immunogenicity of the chosen mutations and long peptide sequences.…”

Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma

“…As test tumor antigens, we used 11 different polypeptides derived from 9 different tumor antigens - MUC-1 (44,45), CEA (45-47), MAGE-3 (45, 48), Her-2/neu (45,49,50), Survivin (45,51), telomerase (45,52), EGFR (53,54), p53 (45,55), and heparanase (50, 56) - expressed in CRC cells. All peptides were designed in such a way that they contain a previously described immunogenic HLA-A*0201 T cell epitope.…”

Signal 3 Availability Limits the CD8 T Cell Response to a Solid Tumor

“…Tumor-specific CD8 T cells have been isolated from the tumor, draining lymph nodes (DLN), 3 and blood of patients with a variety of types of cancer, yet in these cases the tumor is not being controlled by the immune response (1)(2)(3)(4)(5)(6)(7). Adoptive immunotherapy, using tumorinfiltrating lymphocytes that are expanded in vitro, has been the most successful immunotherapeutic approach thus far and gives reason for optimism that if immune responses can be activated in situ, tumor control could be achieved (8 -13).…”