Monday, April 29, 2024
4/29/2024
PROJECT SUMMARY/ABSTRACT Autoimmune Regulator gene (AIRE) prevents autoimmunity by promoting thymic deletion of self-reactive T cells. While most studied in the thymus, AIRE is also expressed in secondary lymphoid organs, where it is thought to contribute to peripheral tolerance through interaction with and deletion of self-reactive T cells. However, AIRE’s role in extrathymic Aire-expressing cells (eTACs) is likely more multi-faceted than in the thymus. We recently identified AIRE expression in multiple myeloid populations in the tumor microenvironment (TME). These include dendritic cells (DCs) and monocytes, but are predominantly composed of tumor associated macrophages (TAMs), which are known to inhibit anti-tumor immune responses. While tumor associated eTACs were only recently discovered by our group, prior work implicates AIRE in inhibiting anti-tumor immunity. Recently available tools to study AIRE in mice have facilitated investigation of peripheral AIRE expression in the TME. We have found tumor associated eTACs in several common solid tumor models expressing myeloid lineage markers by both flow cytometry and mass cytometry (CyTOF). Critically, we also demonstrated that ablation of Aire+ cells dramatically slows tumor progression. This preliminary data together with the therapeutic potential for targeting eTACs in the TME to improve cancer immunotherapy make this a population deserving of thorough functional investigation. This proposal will test the hypothesis that tumor associated eTACs are an immunosuppressive, pro-tumoral cell population. Aim 1 of this proposal will define the phenotypic and transcriptional profiles of tumor associated eTACs, as well as their spatial organization. Aim 2 will determine the mechanism by which Aire+ cells can promote tumor progression. Aim 3 will define the signals that drive Aire expression and elucidate the cell-intrinsic role of Aire in tumor associated eTACs. This research approach will be carried out using a variety of methods including single cell analysis via RNA-seq, CyTOF, flow cytometry and in vivo assays utilizing novel genetic mouse models. These proposed studies will be the first characterization of AIRE expression in any tumor resident immune cells and will further our understanding of the function of peripheral AIRE-expressing cell types. This could result in the discovery of novel pathways relevant to therapeutic resistance and improve our understanding of global AIRE function. Translationally, this work may identify novel immune targets for cancer therapies. This research project and fellowship training will be conducted at a top-funded research institution, the University of California, San Francisco (UCSF), in the laboratories of Dr. James Gardner and Dr. Matthew Spitzer, with expert mentorship from Dr. Vasilis Ntranos. Dr. Gardner has expertise in the study of peripheral AIRE and mouse model generation. Dr. Spitzer has expertise in systems immunology and tumor infiltrating myeloid cell biology. Dr. Ntranos has expertise in computational analysis of single cell datasets. Overall, this facility and team provide a rich training environment for completion of this research and development of professional skills necessary for a career in academic research.
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