Background: SR-A was recently shown to be a receptor on antigen presenting cells for heat shock proteins (HSPs), and was implicated in the cross-presentation of HSP-chaperoned antigens. This receptor has largely been studied in the context of atherosclerosis as well as innate immunity against pathogens. Here we evaluated the role of SR-A in generation of anti-tumor immunity following vaccination with HSP (i.e., grp170)-based vaccines.

Methods: Wild type and SR-A^-/- C57BL6 mice were immunized with HSP-based vaccine formulations, followed by challenge with antigen-expressing B16 melanoma cells. Vaccine consisted of large stress protein grp170 derived from B16 tumor, B16 cell-expressing grp170, and melanoma antigen gp100 complexed to grp170 through the use of heat shock. Antigen-specific T-cell frequency was assayed by ELISPOT. Dendritic cell function was measured by stimulation of antigen specific T-cells, and cytokine production via ELISA.

Results: We observed that SR-A is not required for antitumor immunity generated by this HSP. Surprisingly, the lack of SR-A (in SR-A knockout mice) was associated with significantly enhanced adjuvant, i.e., HSP or lipopolysaccharide (LPS), elicited vaccine activities against poorly immunogenic tumors. Moreover, SR-A deficiency promotes an antigen-specific T-cell response in SR-A knockout mice following vaccination. The SR-A deficient dendritic cells are more responsive to inflammatory stimuli and display a more effective antigen presenting capability compared to wild-type cells.

Conclusions: SR-A is able to attenuate immunostimulatory effects of adjuvants or ‘danger’ molecules in vivo. In view of the fact that SRA is only one of scavenger receptors that bind grp170, we propose that different scavenger receptor interactions with HSP lead to distinct immunological consequences. Understanding this interplay of HSP receptors and their regulation of a specific immune response has important clinical implications in heat shock protein vaccine design for cancer immunotherapy.