Inhibition of tumor growth and metastasis by EMMPRIN multiple antigenic peptide (MAP) vaccination is mediated by immune modulation

Abstract

ABSTRACTPreviously, we have identified a new epitope in EMMPRIN, a multifunctional protein that mediates tumor cell–macrophage interactions and induces both MMP-9 and VEGF. Here, we synthesized this epitope as an octa-branched multiple antigenic peptide (MAP) to vaccinate mice implanted with subcutaneous syngeneic colon (CT26), prostate (TRAMP-C2) or renal (RENCA) cell line carcinomas. Vaccination inhibited, and sometimes regressed, tumor growth in a dose-dependent manner, reaching 94%, 71% and 72% inhibition, respectively, at a 50 μg dose (p < 0.01). Mice with regressed tumors demonstrated immune memory, preventing tumor recurrence upon re-implantation (p < 0.001). When tumor cells were administered through the tail vein to generate lung metastases, vaccination reduced the number of metastatic foci (by 15- and 23-folds, p < 0.001), and increased the median survival time by 25% and 53% in RENCA and CT26 metastases, respectively (p < 0.01) relative to scrambled-MAP controls. No significant adverse responses were observed in all experiments. We show that the tumor microenvironment was immune modulated, as vaccination induced production of EMMPRIN-specific antibodies, increased CD8+ T cells infiltration and cytotoxicity, alleviated immune suppression by decreasing TGFβ concentrations, reduced angiogenesis and cell proliferation, and enhanced apoptosis. Thus, our successful active peptide vaccination strategy differs from previous, unsuccessful attempts, both in the selected target (the EMMPRIN epitope) and in the use of a modified, MAP configuration, and demonstrates that this may be an efficient approach for the treatment and prevention of some types of cancer.