Therapeutic potential of T cell responses against tumor initiating cell-associated antigens in CRC

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Survival of colorectal carcinoma (CRC) patients is determined by the establishment of metastases. These arise from a small subpopulation of long term tumor-initiating cells (LTTIC). The extent of T cell infiltrates in tumor lesions represents the major prognostic parameter in CRC suggesting clinical relevance of T cell based tumor immune surveillance. We demonstrated that T cell enrichment and effector function in situ is restricted to the population of tumor antigen specific T cells. Activation and function of antigen specific effector T cells can be inhibited by tumor specific regulatory T cells (Treg) which thus may play a critical role during T cell based immune surveillance and control of CRC progression. We hypothesize that efficient immune surveillance and improved CRC prognosis is based on T cell responses against tumor antigens (TA) expressed on LT-TIC. During the first funding period we established a whole proteome-based technology by which we identified new entities of T cell target antigens on primary and metastatic CRC that are differentially expressed throughout the metastatic cascade, some of them being selectively expressed on LT-TIC. T cell responses against these antigens were much more abundant in CRC patients than T cell responses against “canonical” TAs. We further established a method to determine the specificities of spontaneous Treg responses in CRC patients and by this characterized major target antigens of tumor-specific Treg and their functional impact on TA reactive memory T cells. Throughout the second funding period we will investigate the hypothesis that treatment of xenotransplanted TIC spheroids in vivo with LT-TIC specific CTL clones in contrast to CTL specific for canonical CRC associated TAs will result in reduced metastatic potential and tumorigenicity. In addition, we will expand the gained information on LT TIC-associated CRC antigens to investigate the hypothesis that high T cell infiltrates in primary and metastatic CRC are associated with increased numbers of LT-TIC specific T cells and improved prognosis.