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

Abstract

Previously, 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 ( < 0.01). Mice with regressed tumors demonstrated immune memory, preventing tumor recurrence upon re-implantation ( < 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, < 0.001), and increased the median survival time by 25% and 53% in RENCA and CT26 metastases, respectively ( < 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.

Function of miR-146a-5p in Tumor Cells As a Regulatory Switch between Cell Death and Angiogenesis: Macrophage Therapy Revisited

“…In addition, nitrites were accumulated in tumors receiving the combined stimulation, suggesting a shift in macrophage activation. We have recently shown that TGFβ is the dominant cytokine in the RENCA TME ( 41 , 42 ). Therefore, its reduced levels together with the increased macrophage production of NO, altered the TME, alleviated immune suppression and allowed CD8 + T cells to infiltrate deep into the tumor and eradicate tumor cells.…”

Inducing regulated necrosis and shifting macrophage polarization with anti-EMMPRIN antibody (161-pAb) and complement factors

“…21,22 Here we show that 161-pAb and complement are sufficient to induce regulated necrotic death that resembles necroptosis. Because necroptosis has been associated with induction of ICD,42 and based on our previous results, we propose that the 161-pAb with complement can induce ICD in vivo.…”

Peer Review #3 of "Application of built-in adjuvants for epitope-based vaccines (v0.1)"

“…Manuscript to be reviewed presentation on MHC I and II molecules and enhance their immunogenicity, these vaccines continue to fail to demonstrate adequate efficacy or improve the overall survival rate (Simanovich et al, 2017). To solve this problem, epitopes can be displayed on a multiple antigenic peptide (MAP) system which contains a core matrix of lysine residues that form a scaffold (Tam, 1988).…”

“…The results showed that the three HCV envelope MAP peptides exhibit strong immunogenicity and produce higher levels of neutralizing antibodies (Abdelhafez et al, 2017). Tumor vaccines based on MAP may also be an effective way to treat and prevent certain types of cancer (Simanovich et al, 2017).…”