Elucidating the Role of AIRE and Tumor Associated Aire-expressing Cells in Tumor Growth and Immune Evasion

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.

Grant Number: 5F31CA288017-03
NIH Institute/Center: NIH
Principal Investigator: Matthew Arvedson