Determining the role of AIRE and AIRE-expressing tumor associated macrophages in tumor growth and immunity

项目总结/文摘

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 CD4+ T cells. However, AIRE’s role in the periphery is likely more multi-faceted than in the thymus. We recently identified AIRE expression in tumor associated macrophages (TAMs), which are known to inhibit anti-tumor immune responses. While Aire-expressing tumor associated macrophages (aTAMs) 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 and aTAMs. We have found aTAMs in several common solid tumor models expressing common macrophage markers (CD11b, F4/80, and CD64) by both flow cytometry and mass cytometry (CyTOF). Additionally, interrogation of several public human RNA-seq datasets supports AIRE expression in tumor resident myeloid cell types. This preliminary data together with the therapeutic potential for targeting aTAMs to improve cancer immunotherapy make this a population deserving of thorough functional investigation. This proposal will test the hypothesis that aTAMs are an immunosuppressive, pro-tumoral cell population. Aim 1 of this proposal will define the phenotypic, transcriptional, and epigenetic profiles of aTAMs. Aim 2 will determine the mechanism(s) driving induction of AIRE expression in aTAMs. Aim 3 will identify the role of aTAMs in regulating local and systemic immune responses during anti-tumor immunity. This research approach will be carried out using a variety of methods including single cell analysis via RNA-seq, CyTOF, flow cytometry, and ATAC-seq, ex vivo co-cultures, 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 establish 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 further our understanding of global AIRE function. Translationally, this work may identify novel perturbations to improve patient responses to immunotherapy. 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. Matthew Spitzer, Dr. Lewis Lanier, and Dr. James Gardner with expert mentorship from Dr. Matthew (Max) Krummel. Dr. Lanier has made extensive foundational discoveries in immune cell biology. Dr. Spitzer has expertise in systems immunology and single cell methods. Dr. James Gardner has expertise in the study of peripheral AIRE and mouse model generation. Dr. Max Krummel has expertise in tumor myeloid cell biology and cancer immunotherapies. 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.