title: CD204 suppresses large heat shock protein-facilitated priming of tumor antigen gp100-specific T cells and chaperone vaccine activity against mouse melanoma.
abstract: We previously reported that scavenger receptor A (SRA/CD204), a binding structure on dendritic cells (DCs) for large stress/heat shock proteins (HSPs; e.g., hsp110 and grp170), attenuated an antitumor response elicited by large HSP-based vaccines. In this study, we show that SRA/CD204 interacts directly with exogenous hsp110, and lack of SRA/CD204 results in a reduction in the hsp110 binding and internalization by DCs. However, SRA(-/-) DCs pulsed with hsp110 or grp170-reconstituted gp100 chaperone complexes exhibit a profoundly increased capability of stimulating melanoma Ag gp100-specific naive T cells compared with wild-type (WT) DCs. Similar results were obtained when SRA/CD204 was silenced in DCs using short hairpin RNA-encoding lentiviruses. In addition, hsp110-stimulated SRA(-/-) DCs produced more inflammatory cytokines associated with increased NF-κB activation, implicating an immunosuppressive role for SRA/CD204. Immunization with the hsp110-gp100 vaccine resulted in a more robust gp100-specific CD8(+) T cell response in SRA(-/-) mice than in WT mice. Lastly, SRA/CD204 absence markedly improved the therapeutic efficacy of the hsp110-gp100 vaccine in mice established with B16 melanoma, which was accompanied by enhanced activation and tumor infiltration of CD8(+) T cells. Given the presence of multiple HSP-binding scavenger receptors on APCs, we propose that selective scavenger receptor interactions with HSPs may lead to highly distinct immunological consequences. Our findings provide new insights into the immune regulatory functions of SRA/CD204 and have important implications in the rational design of protein Ag-targeted recombinant chaperone vaccines for the treatment of cancer.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Qian
authors.forename: Huanfa
authors.initials: H
authors.lastname: Yi
authors.forename: Chunqing
authors.initials: C
authors.lastname: Guo
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Yu
authors.forename: Daming
authors.initials: D
authors.lastname: Zuo
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.forename: John M
authors.initials: JM
authors.lastname: Kane
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Repasky
authors.forename: John R
authors.initials: JR
authors.lastname: Subjeck
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D020868:Gene Silencing; D050957:HSP110 Heat-Shock Proteins / Q000276:immunology* / Q000378:metabolism; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051117:Scavenger Receptors, Class A / Q000276:immunology* / Q000378:metabolism; D058951:gp100 Melanoma Antigen / Q000276:immunology* / Q000378:metabolism
chemical_list: D019496:Cancer Vaccines; D050957:HSP110 Heat-Shock Proteins; C495140:Msr1 protein, mouse; D051117:Scavenger Receptors, Class A; D058951:gp100 Melanoma Antigen