Identification of tumor and stroma antigens for the treatment of HNSCC

头颈部鳞状细胞癌是一种常见的癌症，预后较差。因此，迫切需要新的治疗策略来治疗这种肿瘤实体。癌症免疫疗法最近作为一种有希望的治疗方式出现在许多癌症中，也可能改善HNSCC患者的临床结果。在其他癌症类型中，自发的肿瘤特异性T细胞反应与肿瘤中T细胞浸润增加、预后改善和对治疗的反应相关，因此可能代表了癌症免疫治疗的一个有希望的资源。对于HNSCC，我们发现自发性肿瘤特异性T细胞反应和T细胞浸润也与预后改善有关。然而，为了在临床上利用肿瘤反应性T细胞的内源性库进行诊断和治疗，必须确定这些反应的靶抗原。我们最近开发了一种新技术，首次允许对肿瘤组织中的T细胞靶抗原进行公正和全面的鉴定，这不仅限于肿瘤细胞相关抗原，而且还可用于鉴定肿瘤基质相关抗原。在这个项目中，我们将确定HNSCC患者肿瘤组织中自发T细胞反应的主要靶抗原，并特别评估肿瘤相关成纤维细胞作为保护性T细胞免疫靶标的作用，因为它们不受免疫编辑，在整个肿瘤组织中均匀表达，并且肿瘤基质对于肿瘤维持和进展是不可或缺的。通过T细胞受体（TCR）测序，我们将确定选定肿瘤细胞和成纤维细胞相关抗原特异性的T细胞是否在肿瘤组织内积累。我们将在更大的HNSCC肿瘤队列中表征选定的主要T细胞靶抗原的表达，并最终评估其与总生存率的预后相关性。在此基础上，我们将选择一组与基于T细胞的癌症免疫治疗潜在相关的hnscc相关抗原。

Head and neck squamous cell carcinoma is a frequent cancer and associated with poor prognosis. Therefore, new therapeutic strategies are urgently required for this tumor entity. Cancer immunotherapy has recently emerged as a promising treatment modality in a number of cancers and may also improve clinical outcome in HNSCC patients. In other cancer types spontaneous tumor-specific T cell responses are correlated with increased T cell infiltration in tumors, improved prognosis and response to treatment and may thus represent a promising resource for cancer immunotherapy. For HNSCC we found that spontaneous tumor specific T cell responses as well as T cell infiltration are also associated with an improved prognosis. However, in order to clinically exploit the endogeneous repertoire of tumor reactive T cells for diagnosis and treatment, determination of the target antigens of such responses is mandatory. We have recently developed a novel technology that for the first time allows an unbiased and comprehensive identification of T cell target antigens in tumor tissues, which is not restricted to tumor cell-associated antigens but can also be used to identify tumor stroma-associated antigens. Within this project we will determine major target antigens of spontaneous T cell responses in the tumor tissue of HNSCC patients and assess in particular the role of tumor-associated fibroblasts as targets of protective T cell immunity since they are not subjected to immune editing, are homogeneously expressed throughout on the whole tumor tissue and since the tumor stroma is indispensable for tumor maintenance and progression. By T cell receptor (TCR) sequencing we will determine whether T cells specific for selected tumor cell- and fibroblast-associated antigens accumulate within the tumor tissue. We will characterize expression of selected major T cell target antigens in a larger cohort of HNSCC tumors and finally assess their prognostic relevance for overall survival. On this basis, we will select a panel of HNSCC-associated antigens with potential relevance for T cell based cancer immunotherapy.