Absence of scavenger receptor A promotes dendritic cell-mediated cross-presentation of cell-associated antigen and antitumor immune response

• Published in: Immunology and cell biology 2012-01, Vol.90 (1), p.101-108
• Main Authors: Guo, Chunqing, Yi, Huanfa, Yu, Xiaofei, Hu, Fanlei, Zuo, Daming, Subjeck, John R, Wang, Xiang‐Yang
• Format: Article
• Language: English
• Subjects: Animals; antigen presentation; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - metabolism; Antigens - genetics; Antigens - immunology; Antigens - metabolism; Bone Marrow Cells - immunology; Bone Marrow Cells - metabolism; CD204; Cell Line, Tumor; Cells, Cultured; Cross-Priming - immunology; Cytokines - immunology; Cytokines - metabolism; dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - transplantation; Flow Cytometry; immune response; Immunotherapy, Adoptive - methods; Inflammation Mediators - immunology; Inflammation Mediators - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms, Experimental - immunology; Neoplasms, Experimental - pathology; Neoplasms, Experimental - therapy; Ovalbumin - genetics; Ovalbumin - immunology; Ovalbumin - metabolism; Phagocytosis - immunology; scavenger receptor; Scavenger Receptors, Class A - deficiency; Scavenger Receptors, Class A - genetics; Scavenger Receptors, Class A - immunology; Tumor Burden - genetics; Tumor Burden - immunology
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1038/icb.2011.10

Given the primary expression of scavenger receptor A (SRA) or CD204 on antigen‐presenting cells, we investigate the immunoregulatory activities of SRA/CD204 in the context of cross‐presentation of cell‐associated antigen and the immunogenicity of dying tumor cells. Immunization with dying prostate cancer cells results in profoundly increased control of subsequently inoculated tumors in SRA/CD204 knockout mice. Using OVA‐expressing RM1 prostate tumor line (RM1‐OVA), we show for the first time that SRA absence greatly enhances dendritic cells (DCs)‐mediated cross‐presentation of OVA antigen derived from dying RM1 cells. While the phagocytic ability of DCs is not significantly impacted by the lack of SRA/CD204, DCs deficient in SRA/CD204 display increased expression of inflammatory cytokines and chemokines, as well as co‐stimulatory molecules upon interaction with dying RM1 cells, implicating a suppressive regulation of the functional activation of DCs by SRA/CD204. Further, SRA/CD204‐deficient DCs pulsed with dying RM1‐OVA cells are more effective than wild‐type counterparts in priming antigen‐specific T‐cell responses, resulting in improved control of RM1 tumor growth in both prophylactic and therapeutic settings. Our findings suggest that the increased immunogenicity of dying tumor cells in SRA/CD204 knockout mice is attributed to the altered functions of DCs in the absence of SRA/CD204, which underscores the important role of SRA/CD204 in host immune homeostasis. Selective downregulation or blockade of this immunoregulatory molecule may lead to enhanced potency of DC‐based vaccines capable of breaking immune tolerance against cancer.