Dendritic Cell Function in the Tumor-Bearing Mouse Uterus

描述(申请人提供)：肿瘤发生可以通过产生被认为是外来实体的抗原来刺激适应性免疫反应。然而，肿瘤进展仍然发生在免疫能力强的个体中，可能是由于抗肿瘤T细胞反应受损。肿瘤微环境中的树突状细胞(TADCs，TADCs)作为适应性免疫反应的主要启动者，可能决定了随后的抗肿瘤T细胞反应是免疫原性的还是耐受性的。TADC功能的丧失可能是由于肿瘤本身表达的因素，肿瘤相关间质的变化，或者肿瘤微环境中存在的其他白细胞群的组成和功能的变化，例如在各种小鼠肿瘤模型和人类癌症中大量存在的髓系衍生抑制细胞(MDSCs)。然而，很少有研究在生理相关的原发肿瘤模型中研究TADC功能障碍，或者MDSCs在促进TADC功能障碍中的作用。因此，这项建议将分析TADC功能的广度--从抗原摄取到抗原特异性T细胞激活--在含有大量MDSC群体的自体子宫内膜癌小鼠模型中。具体目的我将重点介绍子宫引流淋巴结(DLN)中抗原特异性T细胞反应的稳健性和特征，作为整体TADC功能的读数，并将阐述这种反应如何随着肿瘤的进展而变化。然后，《特定目标II》将重点描述在肿瘤微环境和肿瘤-DLN中受损的TADC功能的特定组成部分--即抗原摄取、成熟、迁移、抗原呈递。MDSCs和MDSC衍生因子对TADC功能障碍的贡献也将在每个特定的目标中进行评估，利用体内和体外的测试。糖尿病患者TADC功能障碍相关因素的研究 癌症将转化为基于T细胞的癌症免疫疗法的改进，并可能最终导致基于免疫的癌症预防，因为这两种策略都依赖于功能强大的TADCs来启动和维持抗肿瘤T细胞反应。

DESCRIPTION (provided by applicant): Tumorigenesis can stimulate an adaptive immune response by the production of antigens that are perceived as foreign entities. Nevertheless, tumor progression still occurs in immunocompetent individuals, possibly due to impaired anti-tumor T cell responses. As the primary initiators of the adaptive immune response, dendritic cells (DCs) within the tumor microenvironment (tumor-associated DCs; TADCs) likely establish whether the ensuing anti- tumor T cell response will be immunogenic or tolerogenic. Any loss of TADC function could be due to factors expressed by the tumor itself, changes in the tumor-associated stroma, or changes in the composition and function of other leukocyte populations present within the tumor microenvironment, such as the myeloid-derived suppressor cells (MDSCs) present in large numbers within a variety of murine tumor models and human cancers. However, few studies have examined TADC dysfunction in a physiologically relevant autochthonous tumor model, or the role of MDSCs in promoting TADC dysfunction. This proposal will therefore analyze the breadth of TADC function - from antigen uptake to antigen-specific T cell activation - in a mouse model of autochthonous endometrial carcinoma that harbors a substantial MDSC population. Specific Aim I will focus on the robustness and character of the antigen-specific T cell response in the uterine draining lymph nodes (dLNs) as a readout of overall TADC function, and will address how this response changes with tumor progression. Specific Aim II will then focus on characterizing the specific components of TADC function - i.e. antigen uptake, maturation, migration, antigen presentation - that become impaired within the tumor microenvironment and tumor-dLNs. The contribution of MDSCs and MDSC-derived factors to TADC dysfunction will also be evaluated in each Specific Aim, utilizing both in vivo and in vitro assays. Identification of the factors responsible for TADC dysfunction in cancer will translate to improvements in T cell-based cancer immunotherapies and may ultimately lead to immune- based cancer prevention, as both strategies depend upon functional TADCs to initiate and perpetuate the anti-tumor T cell response.