We are also interested in translating the lessons learned from our basic research in the field of central tolerance into designing novel approaches for immune-based therapies, including cancer immunotherapy. Malignant tumors represent a unique challenge to the immune system, as the immune system primarily regards them as “self-tissues” rather than alien and pathological entities that endanger the organism. Consequently, instead of mounting a rapid and specific immune response against the tumor, the immune system tolerates it (or even actively protects it) via diverse immuno-regulatory mechanisms. Indeed, most recent data suggest that AIRE dysfunction may provide an important advantage in specifically breaking down immunological tolerance to certain tumor-associated antigens and thereby mounting an effective immune response against cancer cells. Therefore, we have also initiated a project in which we aim to exploit breakdown of immunological tolerance in AIRE-deficient individuals for cancer immunotherapy.
Specifically, we have successfully developed an experimental platform for discovery, cloning and generation of autoantibodies that can specifically and potently bind to novel tumor-associated antigens. Indeed, by using this platform, we were able to generate highly potent humanized antibodies (Tennenhouse A, et al, Nat Biomed Eng. 2023), targeting extracellular domains of various membrane-bound antigens associated with different types of tumors (in progress).
