Cancer Immunotherapy Using AIRE Conditioning of the Tumor Epitopeome

T-cell immune tolerance is established in part through the activity of the Auto-immune Regulator (AIRE) transcription factor in the medullary thymic epithelial cells (mTEC) of the thymus. AIRE induces expression of peripheral tissue-specific self-antigens for presentation to naïve T cells to promote activation/deletion of autoreactive T cells. This traditional role of AIRE in mTECs is to prevent autoimmunity. Herein, we demonstrate that tumors mimic the role of AIRE in mTECs to evade immune rejection. We found that AIRE induced a profile of "selfness" at the RNA and protein levels which, when presented on major histocompatibility complexes, shielded the tumor from inherently self-tolerized T cells. Moreover, we describe an in vivo immunotherapy in which engineered changes in AIRE expression in tumor cells altered their profile of selfness, exposing both AIRE-modified and parental unmodified tumor cells to T-cell attack. Therefore, by re-setting the immunological selfness of cancer cells, this AIRE-mediated immunotherapy 1) converted a highly tolerized T-cell compartment into a tumor-reactive T-cell population; 2) conferred upon non-immunogenic tumors de novo sensitivity to immune checkpoint blockade; 3) removed the need to identify potentially immunogenic tumor-associated antigens as targets for generation of T-cell responses; and 4) lead to potent T cell-mediated rejection of aggressive, immunologically cold, non-immunogenic tumors. Patient RNA-sequencing data showed that expression of AIRE predicted response to immune therapies with a strong correlation between AIRE expression and markers of T-cell receptor signaling, suggesting our studies have therapeutic translational value.