Induction of local and systemic immune tolerance towards tumor metastasis through ectopic gene expression in antigen presenting cells of the bone marrow

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Anti-tumor T cell responses are key determinants of improved prognosis in many tumor entities, particularly in regard to protection against tumor relapse and distant metastasis after complete tumor resection. Regulatory T cells (Treg cells) reactive to tumor associated antigens (TAAs) suppress T cell mediated anti-tumor cytotoxicity and their frequencies in cancer patients are negatively correlated to survival. In breast cancer patients bone marrow-resident tumor-specific Treg cells are selectively activated, which initiates their emigration into peripheral tissues where they exert tumor specific immune suppression. The mechanism underlying the activation of TAA-specific Treg cells in bone marrow is hitherto unknown. Our recent findings using transgenic mouse models demonstrate that a unique cell population in bone marrow express the transcription factor autoimmune regulator (Aire) which induces the ectopic expression of peripheral tissue-restricted antigens. Bone marrow-resident Aire-expressing cells (BMACs) express a diverse repertoire of self antigens, including TAAs and genes related to metastasis. By converting naïve TAA-specific CD4+ T cells into Treg cells in bone marrow, BMACs induce in an antigen dependent, MHC-II restricted manner robust populations of TAA-specific Treg cells both in bone marrow and in other lymphoid organs such as spleen. Besides murine models, we detected BMACs in human bone marrow at higher frequencies in cancer patients with various tumor entities than in healthy donors. We here hypothesize that BMACs play a key role in the induction of tumor specific immune tolerance against disseminated cancer cells (DCCs) in bone marrow and metastasizing tumor cells in peripheral tissues. Within this project we aim to investigate (i) the contribution of BMACs on systemic immune tolerance against tumor growth and dissemination via the induction of tumor-reactive Treg cells, (ii) the role of BMACs in creating a tolerogenic niche in bone marrow for the colonization of DCCs, and (iii) the role of tumor derived inflammatory factors for the induction and activation of BMACs, which in turn promote peripheral tolerance against tumor cells. We will exploit Aire-HA and HA-TCR transgenic mouse models along with HA-expressing Balb-NeuT tumor cells, as well as biopsies from cancer patients. With the mouse models we monitor tumor development and tumor cell dissemination in the presence/absence of Aire-HA BMACs. Bone marrow niches where BMACs, Treg cells and DCCs cross-talk with each other will be evaluated in mouse models and biopsies of cancer patients. In order to pinpoint the tumor-derived factors which activate Aire expression in BMACs, we will determine the composition of cytokines in bone marrow and subsequently identify the inflammatory factor as a target to block BMAC activation. We thereby expect to find a potential therapeutic effect of reducing tumor development and metastasis by abrogating BMAC activation and thus Treg induction.