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

结直肠癌（CRC）患者的生存率取决于转移的建立。这些来源于长期肿瘤起始细胞（LTTIC）的一个小亚群。肿瘤病变中T细胞浸润的程度代表CRC的主要预后参数，表明基于T细胞的肿瘤免疫监视的临床相关性。我们证明了原位T细胞富集和效应子功能仅限于肿瘤抗原特异性T细胞群体。抗原特异性效应T细胞的活化和功能可以被肿瘤特异性调节性T细胞（Treg）抑制，因此，Treg可以在基于T细胞的免疫监视和CRC进展的控制期间发挥关键作用。我们假设有效的免疫监视和改善CRC预后是基于T细胞对LT-TIC上表达的肿瘤抗原（TA）的应答。在第一个资助期内，我们建立了一种基于全蛋白质组的技术，通过该技术，我们鉴定了原发性和转移性CRC上T细胞靶抗原的新实体，这些抗原在整个转移级联中差异表达，其中一些在LT-TIC上选择性表达。在CRC患者中，针对这些抗原的T细胞应答比针对“典型”TA的T细胞应答丰富得多。我们进一步建立了一种方法来确定CRC患者中自发Treg应答的特异性，并通过这种方法表征了肿瘤特异性Treg的主要靶抗原及其对TA反应性记忆T细胞的功能影响。在整个第二个资助期内，我们将研究这样的假设，即与典型CRC相关TA特异性CTL相比，用LT-TIC特异性CTL克隆在体内治疗异种移植的TIC球状体将导致转移潜力和致瘤性降低。此外，我们将扩大获得的信息LT TIC相关的CRC抗原，调查原发性和转移性CRC的高T细胞浸润与LT-TIC特异性T细胞数量增加和预后改善相关的假设。

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.