To find the road traveled to tumor immunity: The trafficking itineraries of molecular chaperones in antigen-presenting cells

Molecular chaperones, both endoplasmic reticulum and cytosol derived, have been identified as tumor rejection antigens; in animal models, they can eli cit prophylactic and therapeutic immune responses against their tumor of or igin. Chaperone immunogenic activity derives from three principal character istics: they bind an array of immunogenic (poly)peptides, they can be effic iently internalized by professional antigen-presenting cells, and once inte rnalized, they traffic to a subcellular compartment(s) where peptide releas e can occur. Within the antigen-presenting cell, chaperone-derived peptides can be assembled onto major histocompatibility class I molecules for prese ntation at the antigen-presenting cell surface, thereby yielding the requis ite and specific CD8(+) T-cell responses that contribute to the process of tumor rejection. Though it is clear that chaperones, in particular GRP94 (g p96), calreticulin and Hsp70, can elicit cellular immune responses, the sub cellular basis of chaperone processing by antigen-presenting cells remains mysterious. In this review, we discuss recent reports describing the identi fication of a chaperone internalization receptor and the physiological rele ase of chaperones from necrotic cells, and we present views on the traffick ing pathways within antigen-presenting cells that may function to deliver t he chaperone-associated peptides to subcellular organelles for their subseq uent exchange onto major histocompatibility complex molecules.