title: Efficient presentation of naturally processed HLA class I peptides by artificial antigen-presenting cells for the generation of effective antitumor responses.
abstract: Appropriate presentation of tumor-associated antigens (TAA) by antigen-presenting cells (APC) is required for the development of clinically relevant antitumor T-cell responses. One common approach, which uses APC pulsed with synthetic peptides, can sometimes generate ineffective immune responses. This failure may, in part, be attributed to the formation of HLA/synthetic pulsed peptide complexes that possess different conformations compared with those of endogenously presented peptides. In addition, endogenous peptides may undergo post-translational modifications, which do not occur with synthetic peptides. Because our goal is to induce immunity that can recognize TAA that are endogenously presented by tumors, we designed an APC that would not only express the required immunoaccessory molecules but also naturally process and present target antigenic peptides. In this study, we generated an artificial APC (aAPC) that can endogenously present any chosen HLA-A*0201 (A2)-restricted peptide by processing a fusion protein that contains a unique "LTK" sequence linked to the antigenic peptide. Proteasome-dependent processing is so effective that the presented peptide can be directly eluted from the cell surface and identified by biochemical methods. Furthermore, we found that aAPC, engineered to endogenously present peptide derived from the melanoma antigen MART1, can be used to prime and expand antitumor CTL that target MART1-expressing tumor cells in a HLA-A2-restricted manner. Our engineered aAPC could serve as an "off-the-shelf" APC designed to constitutively express class I-restricted TAA peptides and could be used to generate effective T-cell responses to treat human disease.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. Naoto_Hirano@dfci.harvard.edu
authors.forename: Naoto
authors.initials: N
authors.lastname: Hirano
authors.forename: Marcus O
authors.initials: MO
authors.lastname: Butler
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Xia
authors.forename: Alla
authors.initials: A
authors.lastname: Berezovskaya
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Murray
authors.forename: Sascha
authors.initials: S
authors.lastname: Ansén
authors.forename: Lee M
authors.initials: LM
authors.lastname: Nadler
mesh_terms: D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000951:Antigens, Neoplasm; D015234:HLA-A Antigens / Q000276:immunology*; D015789:HLA-A2 Antigen; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D058965:MART-1 Antigen; D009363:Neoplasm Proteins / Q000276:immunology; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D010446:Peptide Fragments; D011257:Pregnancy Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011257:Pregnancy Proteins; C043219:membrane-associated placental tissue protein 1