Dendritic Cell Function in the Tumor-Bearing Mouse Uterus

描述（由申请人提供）：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正常的个体中，可能是由于抗肿瘤T细胞反应受损。作为适应性免疫反应的主要发起者，肿瘤微环境中的树突状细胞（dc）（肿瘤相关dc； TADCs）可能决定随后的抗肿瘤T细胞反应是免疫原性的还是耐受原性的。任何tdac功能的丧失都可能是由于肿瘤本身表达的因素，肿瘤相关基质的变化，或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源性抑制细胞（MDSCs）。然而，很少有研究在生理相关的原位肿瘤模型中检测tdac功能障碍，或MDSCs在促进tdac功能障碍中的作用。因此，本研究将在含有大量MDSC的子宫内膜癌小鼠模型中分析tdac功能的广度——从抗原摄取到抗原特异性T细胞活化。我将重点关注子宫引流淋巴结（dln）中抗原特异性T细胞反应的稳健性和特征，作为ttac整体功能的一个指标，并将讨论这种反应如何随着肿瘤进展而变化。特异性目标II将重点描述在肿瘤微环境和肿瘤dln中受损的tdac功能的特定组成部分，即抗原摄取、成熟、迁移、抗原呈递。MDSCs和MDSCs衍生因子对tdac功能障碍的贡献也将在每个Specific Aim中进行评估，使用体内和体外分析。确定导致tdac功能障碍的因素

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.