Identification of the active portion of the CCL3 derivative reported to induce antitumor abscopal effect

Abstract

Background and purpose: Intravenous administration of a single amino acid-substituted chemokine CCL3 derivative named eMIP elicits the abscopal effect (an effect distal to the target), after local irradiation at a tumor-bearing site. To distinguish the active portion of eMIP, we tested the antitumor activity of chemically synthesized partial peptides of eMIP. Synthetic peptide has various advantages in its clinical application. Material and methods: Colon26 adenocarcinoma cells were implanted subcutaneously in the right and left flanks of mice. eMIP, CCL3 or any of synthesized peptides was administered intravenously, either after irradiating the right flank. The effect was evaluated by tumor-growth inhibition. Results: Q/C peptide, a synthetic peptide of amino acids 22–51 of eMIP has no chemotaxis-inducing ability but yet enhanced tumor growth inhibition at the non-irradiated sites, recapitulating the effect of eMIP with local irradiation. Co-administration of this peptide and HSP70 also inhibited tumor growth. Conclusions: Q/C peptide maps to the eMIP β-sheet: 3 adjacent anti-parallel strands connected by the β-hairpins, is the active portion of eMIP necessary for an immunomodulatory antitumor effect. This experimental reduction furthers our understanding of the underlying mechanism of the abscopal effect. The data will open the way for therapeutic application of like peptides. Keywords: Abscopal effect, CCL3, eMIP/ECI301, HSP70, Local irradiation, Partial peptide