Die Bedeutung patientenindividueller Antigene bei der T-Zell-Antwort gegen kolorektale Tumore

T cell responses in cancer patients correlate with improved prognosis. This effect can partially be attributed to cytotoxic T cells that recognize tumor antigens on cancer cells. Hence, the induction or improvement of such therapeutic tumor antigen-specific T cell responses is a major goal of tumor immunotherapy. So far the target-antigens of relevant prognostic T cell responses are unknown. In this thesis a systematic analysis was performed to identify those antigens that are able to elicit spontaneous T cell responses in patients with colorectal carcinoma. Those responses against the newly identified antigens were then compared, in a larger patient cohort, to T cell responses against established “canonical” tumor antigens that are commonly used for immunotherapy. The establishment of the proteome-based technology PF2D (Protein fractionation in two dimensions) in our group allowed the identification of protein fractions out of lysates from primary and metastatic tumor tissue that were capable to elicit strong T cell responses in ELISpot assays. With mass spectrometry and further ELISpot tests we could identify 21 so far unknown tumor-associated antigens. We could show that the T cell response was directed against different antigens in primary tumors or liver metastasis. Some of the identified antigens were selectively overexpressed on tumor stem cells. Additionally in the blood of these patients there was a higher frequency of T cells specific for the newly identified TAA in comparison with canonical TAA, that have been described in the past. In part two of this thesis we could show that patients suffering from colorectal cancer are able to induce spontaneous T cell responses against mutated forms of tumor-associated antigens. These patients harbor higher frequencies of T cells in the blood that are specific for the mutated forms compared to the corresponding wildtyp antigens and they show an increased immune response. This work shows that classical tumor-associated antigens play a minor role in the immune response against tumors. Patient-individual antigens, a result of the unique tumor development in every patient, are highly immunogenic and serve as better targets for immune monitoring and directed T cell therapies