This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Calreticulin (CRT) and gp96 (GRP94) are endoplasmic reticulum-derived molecular chaperones that have been identified as tumor rejection antigens; in murine models they elicit prophylactic and therapeutic anti-tumor responses and inhibit metastatic progression. The efficacy of chaperones in raising immune responses against a broad variety of murine tumors has led to the current phase-III clinical trials for human melanoma and renal carcinoma. Antigen-presenting cells (APCs) are required for chaperone-mediated anti-tumor responses, which appear to derive from: 1) stimulating antigen-independent innate immune responses including APC maturation, activation and cytokine secretion, and 2) activating the adaptive immune system by eliciting peptide-specific immune responses against associated antigens. At present, the mechanisms by which chaperones elicit these responses are poorly understood. The broad objective of the proposed studies is to define the mechanisms by which chaperones elicit immune responses from APC. We will do so by investigating: 1) How do chaperones access the APC MHC class-I antigen presentation pathway? 2) What is the contribution of Scavenger Receptor Class-A in mediating chaperone-elicited immune responses? These areas of investigation evoke from, and are united by, our recent identification of a novel role for scavenger receptors, SR-A and SREC-1 in particular, as endocytic receptors of both gp96 and CRT on APC: expression of Scavenger Receptor Class-A (SR-A) was sufficient to confer chaperone uptake, while SR-A-/- macrophages were impaired in this function. Additionally, SR-A ligands competed for cross-presentation of gp96-associated peptides. On the basis of these findings, we hypothesize that scavenger receptors function in mediating the immune responses stimulated by gp96 and CRT. This grant proposal focuses on elucidating the mechanisms by which scavenger receptors mediate the immunological effects of chaperones; in particular, how SRs traffic chaperones, and their associated peptides, into the antigen presentation pathway. We will test this using cellular and molecular techniques to identify the mechanisms by which chaperone complexes elicit antigen-specific responses, and genetic and immunological techniques to evaluate the contribution of scavenger receptors towards chaperone-mediated antigen presentation. Results derived from these studies will contribute to the understanding of chaperones as immunological molecules. Additionally, insights obtained will benefit the field of immunotherapy by elucidating the underlying mechanisms of a treatment that is currently undergoing clinical evaluation, and will further facilitate the rational development and application of anti-tumor therapy.
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