title: Targeted coating with antigenic peptide renders tumor cells susceptible to CD8(+) T cell-mediated killing.
abstract: The potency of immunotherapies targeting endogenous tumor antigens is hindered by immune tolerance. We created a therapeutic agent comprised of a tumor-homing module fused to a functional domain capable of selectively rendering tumor cells sensitive to foreign antigen-specific CD8(+) T cell-mediated immune attack, and thereby, circumventing concerns for immune tolerance. The tumor-homing module is comprised of a single-chain variable fragment (scFv) that specifically binds to mesothelin (Meso), which is commonly overexpressed in human cancers, including ovarian tumors. The functional domain is comprised of the Fc portion of IgG2a protein and foreign immunogenic CD8(+) T cell epitope flanked by furin cleavage sites (R), which can be recognized and cleaved by furin that is highly expressed in the tumor microenvironment. We show that our therapeutic protein specifically loaded antigenic epitope onto the surface of mesothelin-expressing tumor cells, rendering tumors susceptible to antigen-specific cytotoxic CD8(+) T lymphocytes (CTL)-mediated killing in vitro and in vivo. Our findings have important implications for bypassing immune tolerance to enhance cancer immunotherapy.
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Tae Heung
authors.initials: TH
authors.lastname: Kang
authors.forename: Barbara
authors.initials: B
authors.lastname: Ma
authors.forename: Connie
authors.initials: C
authors.lastname: Wang
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003001:Cloning, Molecular; D004847:Epithelial Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D045683:Furin / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000276:immunology*; D005805:Genes, MHC Class I; D007074:Immunoglobulin G / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D000090204:Mesothelin; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D057127:Single-Chain Antibodies / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D058851:GPI-Linked Proteins; D007074:Immunoglobulin G; C000715528:Msln protein, mouse; D057127:Single-Chain Antibodies; D045683:Furin; D000090204:Mesothelin