Abstract
Transforming growth factor β (TGF-β) is a powerful promoter of cancer progression and a key target for antitumor therapy. As cancer cells exhibit active cholesterol metabolism, high density lipoproteins (HDLs) appear as an attractive delivery system for anticancer TGFβ-inhibitory molecules. We constructed a plasmid encoding a potent TGF-β-blocking peptide (P144) linked to apolipoprotein A-I (ApoA-I) through a flexible linker (pApoLinkerP144). The ApoLinkerP144 sequence was then incorporated into a hepatotropic adeno-associated vector (AAVApoLinkerP144). The aim was to induce hepatocytes to produce HDLs containing a modified ApoA-I capable of blocking TGF-β. We observed that transduction of the murine liver with pApoLinkerP144 led to the appearance of a fraction of circulating HDL containing the fusion protein. These HDLs were able to attenuate TGF-β signaling in the liver and to enhance IL-12 -mediated IFN-γ production. Treatment of liver metastasis of MC38 colorectal cancer with AAVApoLinkerP144 resulted in a significant reduction of tumor growth and enhanced expression of IFN-γ and GM-CSF in cancerous tissue. ApoLinkerP144 also delayed MC38 liver metastasis in Rag2−/−IL2rγ−/− immunodeficient mice. This effect was associated with downregulation of TGF-β target genes essential for metastatic niche conditioning. Finally, in a subset of ret transgenic mice, a model of aggressive spontaneous metastatic melanoma, AAVApoLinkerP144 delayed tumor growth in association with increased CD8+ T cell numbers in regional lymph nodes. In conclusion, modification of HDLs to transport TGF-β-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms.
Highlights
Transforming growth factor b (TGF-b) has long been recognized as a key promoter of tumor growth and a critical initiator of the metastatic process [1]
Consonant with the fact that apolipoprotein A-I (ApoA-I) is the main protein of high density lipoproteins (HDLs), here we show that transduction of the liver with a vector encoding ApoLinkerP144 leads to the secretion of HDLs with TGF-b blocking properties and that this strategy is an efficient therapy to inhibit the growth of liver tumor metastases
Two plasmids were used: one containing P144 bound to a secretory signal peptide and another with P144 linked to ApoA-I through a flexible linker
Summary
Transforming growth factor b (TGF-b) has long been recognized as a key promoter of tumor growth and a critical initiator of the metastatic process [1]. Most established tumors develop mutations in the TGF-b-signaling pathway These mutations confer the tumor cells the possibility of bypassing TGF-b– mediated growth inhibition while making use of the ability of this cytokine to enhance tumor growth, invasion, and metastasis [2]. TGF-b stimulates tumor invasion and metastasis by inhibiting anti-tumor immune surveillance and promoting local immune suppression. Along this line, TGF-b directly inhibits NK and T cell proliferation and suppresses CD8+ T cell cytotoxicity by transcriptional repression of genes encoding perforin, granzymes and cytotoxins [7]. Attempts to antagonize TGF-b in malignant processes were not followed by clear clinical benefit and clinical development of two of the three products which reached phase II were discontinued [8]
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