Abstract
The cell surface receptor CD91/LRP-1 binds to immunogenic heat shock proteins (HSP) and α2M ligands to elicit T cell immune responses. In order to generate specific immune responses, the peptides chaperoned by HSPs or α2M are cross-presented on MHC molecules to T cells. While the immunogenic HSPs naturally chaperone peptides within cells and can be purified as an intact HSP-peptide complex, the peptides have had to be complexed artificially to α2M in previous studies. Here, we show that immunogenic α2M-peptide complexes can be isolated from the blood of tumor-bearing mice without further experimental manipulation in vitro demonstrating the natural association of tumor antigens with α2M. The naturally formed immunogenic α2M-peptide complexes are effective in prophylaxis and therapy of cancer in mouse models. We investigate the mechanisms of cross-presentation of associated peptides and co-stimulation by APCs that interact with α2M. These data have implications for vaccine design in immunotherapy of cancer and infectious disease.
Highlights
CD91/LRP-1 is a cell surface receptor in the scavenger receptor family that binds to and internalizes a number of diverse ligands including the heat shock proteins gp96, hsp70, hsp90 and calreticulin and the blood protein a2M [1,2,3]
The antigenically distinct MethA tumor was used as a source of irrelevant peptides. a2M was purified from serum of naıve BALB/c mice to apparent homogeneity as demonstrated by gel electrophoresis and immunoblotting (Fig. 1a, inset). a2M-peptide complexes were formed by very mild heat treatment as previously described [15,20]
CMS5-derived peptides alone or a2M complexed to irrelevant peptides were unable to affect tumor growth demonstrating the requirement for the CD91/LRP-1-binding chaperone and the specificity provided by the peptides
Summary
CD91/LRP-1 is a cell surface receptor in the scavenger receptor family that binds to and internalizes a number of diverse ligands including the heat shock proteins gp, hsp, hsp and calreticulin and the blood protein a2M [1,2,3]. The binding to, and internalization of the HSPs or a2M by CD91/LRP-1 leads to processing of peptides that are chaperoned by these proteins and the presentation of the resultant peptides on MHC I and MHC II molecules [1,2,4,5,6]. Other receptors for the immunogenic HSPs [7] and a2M [8] have been proposed as well as other mechanisms for HSP uptake [9]. A comprehensive discussion on the HSP receptors has been reviewed elsewhere [10]. Immunization with CD91/LRP-1 ligands provides the opportunity to vaccinate against, and treat, cancer and infectious disease [11,12,13]
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