Molecular Targets of the Anti-Tumor T Cell Response

T. Wölfel, V. Lennerz, M. Fatho et al.

III. Medizinische Klinik (Dir.: Ch. Huber), Universität Mainz, Langenbeckstr.1, D-55101 Mainz, Germany

We are still far from understanding the pathways leading to anti-tumor immunity or to its failure. Until now the study of tumor-host interactions relied mainly on the knowledge of T cell epitopes processed from structurally normal shared tumor antigens and presented by frequent HLA alleles. The individuality of tumor-host interactions was largely ignored. It comprises the reactivity towards mutated antigens, expressed by the individual tumor, but also towards unknown epitopes of structurally normal antigens, e.g. presented by rare HLA alleles. We have analysed the spectrum of antigens recognized by autologous CD8-positive T cells in two melanoma patients. For these analyses we generated series of autologous mixed lymphocyte-tumor cell cultures (MLTC) that were cryopreserved at various time points. The MLTC responders were tested for recognition of known shared melanoma antigens in association with the patients´ HLA class I alleles and were also used for cDNA library screening. We found in these model systems that a minority of anti-melanoma T cells was directed against peptides processed from known shared antigens. The majority recognized mutated peptide antigens resulting from somatic point mutations in the patients´ tumor cells. Especially in patient-oriented research it may be critical to identify the preferential targets of the individual anti-tumor T cell repertoire, which will allow for a comprehensive immune monitoring of tumor patients and will finally help to find more effective ways for the induction of anti-tumor immunity in patients.