Spontaneous Systemic T Cell Responses in Cancer Patients

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During the last few years, numerous studies have emerged that clearly demonstrate the spontaneous induction of functional, TAA-specific T cell responses in many tumor patients. We observed in the bone marrow of mice bearing disseminated lymphoma cells TAA-reactive CD8 T cells that conferred protection against (i) expansion of tumor cells in situ as well as (ii) against the formation of distant metastases [6, 7]. Based on this observation, we analyzed the possibility that the presence of tumor antigen in the bone marrow might also trigger the generation of functional, tumor-specific T cells in tumor patients. We therefore evaluated by HLA-tetramer analyses as well as by short term IFN-y Elispot assays the presence of such cells in the peripheral blood and bone marrow of breast cancer patients [8]. We detected high frequencies of tumor-specific CD8 T cells in the blood and bone marrow of most patients. However, only BM-resident T cells exerted functional capacities such as IFN-y secretion or cytotoxic activity. Altogether, T cells reactive against the entirety of TAAs in autologous tumor cells (as presented by autologous tumor cell lysate-pulsed dendritic cells) could be detected in app. 40% of primary operated breast cancer patients. These T cells existed in frequencies of 1:200 to 1:10,000 of total T cells and included cytotoxic CD8+ T cells as well as CD4+ T helper cells. Similar frequencies of tumor-reactive T cells were detected in patients with different tumors. Using the IFN-y Elispot assay, we investigated reactivity of T cells from bone marrow and peripheral blood to melanoma lysate-pulsed autologous DCs in melanoma patients [9]. We detected tumor-reactive T cells in altogether 25% of the patients. In the bone marrow, melanoma-reactive T cells were present in 18% while in peripheral blood such cells were present in only 10% of the patients.

Pancreatic cancer is characterized by aggressive growth and treatment resistance. A dominance of TH2 cytokines in patients' sera, as reported previously, suggests systemic tumor-induced immunosuppression, potentially inhibiting the induction of tumor-reactive T cells. Despite these potentially powerful immunosup-pressive factors we detected high numbers of tumor-reactive T cells in 100% of bone marrow samples and in 50% of the blood samples of pancreatic cancer patients [10]. These comprised CD8 and CD4 T cells which secreted the TH1 cytokine IFN-y rather than TH2 cytokines and exerted cytotoxic capacity upon stimulation with tumor antigens [10, 11]. Freshly isolated T cells from cancer patients recognized autologous tumor cells and the pancreatic cancer-associated tumor antigen MUC1. Thus, tumor antigen-specific T cell responses occur regularly during pancreatic cancer disease and lead to enrichment of tumor cell-reactive memory T cells in the bone marrow.

Besides carcinomas, hematological malignancies can also be recognized by the immune system and lead to the induction of spontaneous T cell responses. We analyzed bone marrow and peripheral blood of HLA-A2-positive multiple myeloma (MM) patients for the presence and functional activity of CD8 T cells specific for the MUC1-derived peptide LLLLTVLTV [12]. 40% of the patients with MM contained elevated frequencies of MUC1-specific CD8 T cells in freshly isolated samples from peripheral blood (PB) or bone marrow (BM) compared with corresponding samples from healthy donors. Similar to our findings from breast carcinoma, pancreatic carcinoma and malignant melanoma, BM-residing T cells possessed a higher functional capacity upon specific reactivation than PB-derived T cells with regard to IFN-y secretion, perforin production, and cytotoxicity.

It can therefore be concluded that virtually all tumor types induce spontaneous and functional T cell responses. These result in the accumulation of tumor-reactive T cells especially in lymphoid organs such as the BM.

Detailed phenotypic analyses revealed that the majority (approximately 70%) of tumor-specific BM T cells belonged to the population of memory T cells, including app. 40% of central- and 60% of effector memory T cells [13]. The presence of effector memory T cells is particularly interesting, since this subset is generated by appropriate reactivation of long-lived bone marrow-resident central memory T cells that subsequently differentiate into the rather short-lived latter subset and are capable of mediating protective effector functions. Thus, the dominance of effector memory T cells in the bone marrow of cancer patients suggests that presentation of tumor antigens to T cells is a rather frequent event in the BM parenchyme.

In order to characterize the memory T cell repertoire of tumor patients in more detail, we analyzed the bone marrow of primary operated breast cancer patients and healthy female donors for the presence and frequencies of spontaneously induced effector/memory T lymphocytes with peptide-HLA-A2-restricted reactivity against 10 different breast TAAs and a variety of normal breast tissue-associated antigens by short-term IFN-y Elispot analysis [14]. 67% of these patients recognized TAAs with a mean frequency of 1:7,000. TAA reactive T cells recognized simultaneously an average of half 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 (pp. 141-149) to only 25% recognition of MUC1 (pp. 12-20) or Her-2/neu (pp. 369-377). In comparison with TAAs, reactivity to normal breast tissue-associated antigens was lower with respect (i) to the proportions of responding patients (30%) and (ii) to the frequency of T cells recognizing the normal tissue antigens (only 1:12,000 T cells). Interestingly, 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. Thus, the natural repertoire of tumor-reactive memory T cells in the BM of cancer patients is polyvalent and highly individual and compared to healthy individuals clearly shifted towards tumor recognition. Taken together, the bone marrow appears as a lymphatic organ particularly involved in the induction and/or maintenance of natural T cell immunity against tumor antigens.

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