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Novel properties of antigen receptors and instruments to modulate lymphoid function in physiological and pathological conditions

Final Report Summary - NOVARIPP (Novel properties of antigen receptors and instruments to modulate lymphoid function in physiological and pathological conditions)

In the ERC-funded NOVARIPP project we have addressed important questions that have meant a significant shift in paradigms, altering how we think that T lymphocytes, a white blood cell fundamental to fight infections and cancer, see and respond to pathogens. In addition, we have investigated the relevance of the protein RRAS2 in physiological processes of T and B lymphocytes as well as in pathogenic situations. Our most prominent results show that the T cell receptor (TCR), a protein complex of T lymphocytes responsible for the recognition of proteins (antigens) derived from pathogens, acts in a coordinated manner: the TCRs that bind antigen inform the other unbound TCRs in a way that all, bound and unbound, participate in the activation of T lymphocytes. Another important result is that RRAS2 is a “driver” oncogene, i.e. a gene whose alteration is sufficient to push the transformation of normal cells into cancerous ones. Even more interesting is that RRAS2 causes cancer without the need to bear activating, “oncogenic”, mutations: the sole overexpression of the wild type gene causes cancer. Thus, RRAS2 drives cancer in a different way to the well-known oncogene KRAS which requires activating mutations. In addition to the discoveries on how the TCR sees antigen and the role of RRAS2 in cancer we have investigated new avenues to alter the pathogenic response of T lymphocytes to self-antigens and to inhibit the activity of RRAS2. These approaches have led to the development of two drugs that are being directed towards clinical trials in important human diseases.