MMP11: a novel target antigen for cancer immunotherapy.
OBJECTIVE
Matrix metalloproteinases (MMP) are zinc-dependent endopeptidases that mediate numerous physiologic and pathologic processes, including matrix degradation, tissue remodeling, inflammation, and tumor metastasis. To develop a vaccine targeting stromal antigens expressed by cancer-associated fibroblasts, we focused on MMP11 (or stromelysin 3). MMP11 expression correlates with aggressive profile and invasiveness of different types of carcinoma.


METHODS
To show the efficacy of a vaccine targeting MMP11, we constructed a series of plasmid DNA vectors expressing murine MMP11. Mice were vaccinated by i.m. injection followed by in vivo DNA electroporation. A chemically induced, MMP11-overexpressing colon cancer model was established and characterized. Antibody and T-cell responses were determined, and immunoreactive epitopes were characterized. To analyze the possible use of MMP11 as tumor-associated antigen in cancer patients, HLA-A2.1 transgenic mice (HHD) were used to identify reactive epitopes as tools to assess immunogenicity in humans.


RESULTS
Using microarray, we confirmed the overexpression of MMP11 mRNA in a large panel of human tumor samples. MMP11 vaccine induced cell mediated and antibody immune response and exerted significant antitumoral protection in mice with colon cancer in prophylactic and therapeutic settings. HHD transgenic mice were vaccinated with a plasmid encoding human MMP11, and a HLA-A2.1--restricted epitope (hMMP(237)) was identified. hMMP(237) was shown to be immunogenic in human peripheral blood mononuclear cells (PBMC) by in vitro priming.


CONCLUSIONS
Our study describes the identification of MMP11 as a novel broadly expressed tumor associated antigen as target candidate for cancer immunotherapy.
Peruzzi
Daniela
D
Istituto di Ricerca di Biologia Molecolare-Merck Research Laboratories, Rome, Italy.
Mori
Federica
F
Conforti
Antonella
A
Lazzaro
Domenico
D
De Rinaldis
Emanuele
E
Ciliberto
Gennaro
G
La Monica
Nicola
N
Aurisicchio
Luigi
L
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D000939:Epitopes / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D053507:Matrix Metalloproteinase 11 / Q000276:immunology*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D014162:Transfection
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000939:Epitopes; D015789:HLA-A2 Antigen; D061965:Matrix Metalloproteinase Inhibitors; D053507:Matrix Metalloproteinase 11