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The cell surface receptor CD91/LRP-1 binds to immunogenic heat shock proteins (HSP) and α(2)M ligands to elicit T cell immune responses. In order to generate specific immune responses, the peptides chaperoned by HSPs or α(2)M 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 α(2)M in previous studies. Here, we show that immunogenic α(2)M-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 α(2)M. The naturally formed immunogenic α(2)M-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 α(2)M. These data have implications for vaccine design in immunotherapy of cancer and infectious disease.