title: Cancer immunotherapy targeting the high molecular weight melanoma-associated antigen protein results in a broad antitumor response and reduction of pericytes in the tumor vasculature.
abstract: The high molecular weight melanoma-associated antigen (HMW-MAA), also known as melanoma chondroitin sulfate proteoglycan, has been used as a target for the immunotherapy of melanoma. This antigen is expressed on the cell surface and has a restricted distribution in normal tissues. Besides its expression in a broad range of transformed cells, this antigen is also found in pericytes, which are important for tumor angiogenesis. We generated a recombinant Listeria monocytogenes (Lm-LLO-HMW-MAA-C) that expresses and secretes a fragment of HMW-MAA (residues 2,160-2,258) fused to the first 441 residues of the listeriolysin O (LLO) protein. Immunization with Lm-LLO-HMW-MAA-C was able to impede the tumor growth of early established B16F10-HMW-MAA tumors in mice and both CD4(+) and CD8(+) T cells were required for therapeutic efficacy. Immune responses to a known HLA-A2 epitope present in the HMW-MAA(2160-2258) fragment was detected in the HLA-A2/K(b) transgenic mice immunized with Lm-LLO-HMW-MAA-C. Surprisingly, this vaccine also significantly impaired the in vivo growth of other tumorigenic cell lines, such as melanoma, renal carcinoma, and breast tumors, which were not engineered to express HMW-MAA. One hypothesis is that the vaccine could be targeting pericytes, which are important for tumor angiogenesis. In a breast tumor model, immunization with Lm-LLO-HMW-MAA-C caused CD8(+) T-cell infiltration in the tumor stroma and a significant decrease in the number of pericytes in the tumor blood vessels. In conclusion, a Lm-based vaccine against HMW-MAA can trigger cell-mediated immune responses to this antigen that can target not only tumor cells but also pericytes in the tumor vasculature.
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6076, USA.
authors.forename: Paulo Cesar
authors.initials: PC
authors.lastname: Maciag
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Seavey
authors.forename: Zhen-Kun
authors.initials: ZK
authors.lastname: Pan
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Paterson
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D019496:Cancer Vaccines / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D007111:Immunity, Cellular / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D008089:Listeria monocytogenes / Q000378:metabolism; D008546:Melanoma, Experimental / Q000098:blood supply / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000473:pathology*; D020286:Pericytes / Q000276:immunology / Q000473:pathology*; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D011994:Recombinant Proteins; D000099216:Chondroitin Sulfate Proteoglycan 4