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.
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.
|Blaisdell, Adam; Crequer, Amandine; Columbus, Devin et al. (2015) Neutrophils Oppose Uterine Epithelial Carcinogenesis via Debridement of Hypoxic Tumor Cells. Cancer Cell 28:785-99|