ABSTRACT
It is gradually becoming apparent, given the molecular identification of most tumor antigens as unmutated self proteins, that the most effective strategy for cancer immunotherapy may well be to mobilize the same self-directed immune repertoire thought to mediate pathogenic autoimmunity. Autoimmune damage often includes spreading of the response to additional, previously uninvolved determinants; harnessing a similar expanding response to tumors would be desirable (1). Although the concept of cancer immunotherapy has been around since the pioneering work of William Coley over 100 years ago, several important new considerations have raised the possibility that the immune system can be manipulated for tumor control. The first of these is the tremendous progress made in the molecular definition of cancer antigens, which has finally brought tumor immunology and immunotherapy into the mainstream of immunologic research. The second feature is the existence in normal individuals of an abundant selfdirected T-and B-cell repertoire, which can be mobilized under appropriate conditions to mount an aggressive attack on the self. These potentially autoreactive lymphocytes have evaded negative selection because the determinants they recognize are poorly processed and presented from the native antigen. This hierarchy of determinant presentation and tolerance susceptibility in responding lymphocytes therefore represents another aspect of the recognition of self in cancer immunotherapy. Finally, the role of APC differentiation states in mediating immune activation versus tolerance induction has provided a theoretical framework for active regulation of the selfdirected repertoire. In this chapter, we will consider each of these concepts as they relate to anti-self/anti-tumor immune responses.
