Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 64, Issue 6, Pages 717-725Publisher
SPRINGER
DOI: 10.1007/s00262-015-1681-9
Keywords
Transforming growth factor beta; Apolipoprotein A-I; Colon cancer; Liver; Antitumor immune response
Categories
Funding
- Instituto de Salud Carlos III - FEDER program of the European Union [PI13/00207]
- Miguel Servet contract from Instituto de Salud Carlos III
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Transforming growth factor beta (TGF-beta) promotes tumor growth, invasion and metastasis in established tumors. In this study, we analyzed the effect of overexpressing an anti-TGF-beta peptide fused to apolipoprotein A-I (ApoA-I) as a scaffold molecule. We generated and characterized stable MC38 colon carcinoma clones expressing ApoA-I fused to the anti-TGF-beta peptide P144 and ApoA-I as control cells. We evaluated in vitro the gene expression profile, cell cycle and anchorage-independent growth. The in vivo tumorigenic potential and immunogenicity were analyzed inoculating the MC38 clones into C57BL/6 mice, recombination-activating gene 1 knockout mice or mice deficient in NK cells either subcutaneously or intrasplenically to generate hepatic metastases. While overexpression of ApoA-I had no effect on the parameters analyzed, ApoA-I fused to P144 markedly diminished the tumorigenic capacity and metastatic potential of MC38 in vitro and in vivo, thus generating a highly immunogenic cell line. MC38 cells transfected with ApoA-I fused to P144 triggered memory T cell responses able to eliminate the parental cell line upon re-challenge. In summary, expression of ApoA-I fused to P144 is a novel strategy to modulate TGF-beta in tumor cells. These results highlight the potential of TGF-beta as a target in the development of new antitumor treatments.
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