PROTECTIVE IMMUNITY INDUCED BY TUMOR VACCINES REQUIRES INTERACTION BETWEEN CD40 AND ITS LIGAND, CD154

Interactions between CD40 and its ligand, CD154 (CD40L, gp39), have be en shown to play a central role in the regulation of humoral immunity. Recent evidence suggests that this ligand-receptor pair also plays an important role in the induction of cell-mediated immune responses, in cluding those directed against viral pathogens, intracellular parasite s, and alloantigens. The contribution of this ligand-receptor pair to the development of protective immunity against syngeneic tumors was ev aluated by blocking the in vivo function of CD154 or by studying tumor resistance in mice genetically deficient in CD40 expression (CD40(-/- )). In the former ease, anti-CD154 monoclonal antibody treatment inhib ited the generation of protective immune responses after the administr ation of three potent tumor vaccines: irradiated MCA 105, MCA 105 admi xed with Corynebacterium parvum adjuvant, and irradiated B16 melanoma cells transduced with the gene for granulocyte macrophage colony-stimu lating factor. Confirmation of the role of CD40/CD154 interactions in tumor immunity was provided by the overt tumor susceptibility in CD40- deficient mice as compared to that in CD40(+/+) mice. In this case, wi ld-type but not CD40-deficient mice could be readily protected against live TS/A tumor challenge by preimmunization with TS/A admired with C . parvum. These findings suggest a critical role for CD40/CD154 intera ctions in the induction of cellular immunity by tumor vaccines and may have important implications for future approaches to cell-based cance r therapies.