Exploiting breakdown of self-tolerance to tissue-specific antigens for cancer immunotherapy

The immune system is delicately balanced between its response to millions of diverse pathogens and its tolerance towards thousands of self-antigens. For this end, T lymphocytes are ‘educated’ in the thymus, a primary lymphoid organ, and undergo a process of selection by a rare population termed thymic epethilal cells (TECs). Specifically, medullary thymic epithelial cells (mTECs) play a key role in inducing central tolerance, by their unique capacity to express and present almost all self-antigens, including thousands of peripheral tissue antigens (PTAs). This ability was shown to be largely dependent on a single molecular factor - the autoimmune regulator (Aire). It is well established that Aire-deficient mice on NOD genetic background develop multi-organ autoimmunity, characterized by generation of autoantibodies against various tissue-specific self-antigens. In this regard, mTECs represent an interesting paradigm for the field of cancer immunology, as mTEC-driven induction of central tolerance to self-antigens and immune response against tumor-associated self-antigens could be viewed as opposite sides of the same coin. By harnessing targeted breakdown of self-tolerance to various tissue-specific antigens, as seen in the Aire-deficient mice, we aim to isolate highly specific autoantibodies, which could potentially be exploited as the “magic bullet” to ultimately defeat human tumors. This could present a novel immune strategy for diagnosing and treating cancer.