Dendritic Cell Function in the Tumor-Bearing Mouse Uterus

描述（由申请方提供）：肿瘤发生可通过产生被视为外来实体的抗原来刺激适应性免疫应答。然而，肿瘤进展仍然发生在免疫活性个体中，可能是由于抗肿瘤T细胞应答受损。作为适应性免疫应答的主要起始者，肿瘤微环境内的树突状细胞（DC）（肿瘤相关DC; TADC）可能确定随后的抗肿瘤T细胞应答是免疫原性的还是致耐受性的。TADC功能的任何丧失可能是由于肿瘤本身表达的因子、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体的组成和功能的变化，例如在各种鼠肿瘤模型和人类癌症中大量存在的骨髓源性抑制细胞（MDSC）。然而，很少有研究在生理相关的自体肿瘤模型中检查TADC功能障碍，或MDSC在促进TADC功能障碍中的作用。因此，该提案将分析TADC功能的广度-从抗原摄取到抗原特异性T细胞活化-在含有大量MDSC群体的原位子宫内膜癌小鼠模型中。具体目标I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，作为整体TADC功能的读数，并将解决这种反应如何随肿瘤进展而变化。然后，Specific Aim II将专注于表征TADC功能的特定组分-即抗原摄取，成熟，迁移，抗原呈递-这些组分在肿瘤微环境和肿瘤dLN中受损。还将利用体内和体外试验，在每个特定目标中评价MDSC和MDSC衍生因子对TADC功能障碍的贡献。TADC功能障碍相关因素的鉴定 癌症的治疗将转化为基于T细胞的癌症免疫疗法的改善，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性TADC来启动和维持抗肿瘤T细胞应答。 公共卫生相关性：该提案解决了肿瘤发生和特别是髓源性抑制细胞（MDSC）如何影响组织驻留树突状细胞（DC）启动适应性免疫应答的能力。这些发现将对基于T细胞的癌症免疫疗法产生影响，这些免疫疗法在很大程度上依赖于DC介导的抗原呈递来实现其功效。

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. PUBLIC HEALTH RELEVANCE: This proposal addresses how tumorigenesis and specifically myeloid-derived suppressor cells (MDSCs) affect the ability of tissue-resident dendritic cells (DCs) to initiate an adaptive immune response. These findings will have implications for T cell-based cancer immunotherapies, which rely in large part upon DC-mediated antigen presentation for their efficacy.