PARCC, INSERM, UMR-970, Université de Paris, 56 rue Leblanc, 75015, Paris, France.
Laboratoire de Recherches Biochirurgicales (Fondation Carpentier), Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, 75015, Paris, France.
Cancer Immunol Immunother. 2020 Dec;69(12):2501-2512. doi: 10.1007/s00262-020-02631-7. Epub 2020 Jun 19.
Peptide vaccines represent an attractive alternative to conventional anti-tumor therapies, but have not yet achieved significant clinical efficacy with commonly used formulations. Combination of short antigenic peptides, synthetic melanin and TLR9 agonist (Toll-like receptor 9, CpG-28) was reported as highly efficient to trigger strong CD8 + T-cell responses. We compared this vaccine approach to the standard adjuvant formulation that combines the incomplete Freund's adjuvant (IFA) and CpG-28, using either an ovalbumin epitope (pOVA30) or a spontaneously occurring tumor neoepitope (mAdpgk).Melanin-based vaccine induced significantly higher cytotoxic T lymphocytes (CTL) responses than IFA-based vaccine in both pOVA30- and mAdpgk-targeted vaccines. The anti-tumor efficacy of melanin-based vaccine was further assessed in mice, grafted either with E.G7-OVA cells (E.G7 cells transfected with ovalbumin) or with MC38 cells that spontaneously express the mAdpgk neoepitope. Melanin-based vaccine induced a major inhibition of E.G7-OVA tumor growth when compared to IFA-based vaccine (p < 0.001), but tumors eventually relapsed from day 24. In the MC38 tumor model, no significant inhibition of tumor growth was observed. In both cases, tumor escape appeared related to the loss of antigen presentation by tumor cells (loss of ovalbumin expression in E.G7-OVA model; poor presentation of mAdpgk in MC38 model), although the CTL responses displayed an effector memory phenotype, a high cytolytic potential and low programmed cell death-1 (PD1) expression.In conclusion, synthetic melanin can be efficiently used as an adjuvant to enhance T-cells response against subunit vaccine antigens and compared favorably to the classic combination of IFA and TLR9 agonist in mice.
肽疫苗是一种有吸引力的抗肿瘤治疗替代方法，但使用常用制剂尚未获得显著的临床疗效。短抗原肽、合成黑色素和 TLR9 激动剂（Toll 样受体 9，CpG-28）的组合被报道可高效触发强烈的 CD8+T 细胞反应。我们将这种疫苗方法与标准佐剂制剂进行了比较，该制剂结合了不完全弗氏佐剂（IFA）和 CpG-28，使用卵清蛋白表位（pOVA30）或自发出现的肿瘤新表位（mAdpgk）。与基于 IFA 的疫苗相比，黑色素基疫苗在靶向 pOVA30 和 mAdpgk 的疫苗中均诱导了更高的细胞毒性 T 淋巴细胞（CTL）反应。在 E.G7-OVA 细胞（转染卵清蛋白的 E.G7 细胞）或自发表达 mAdpgk 新表位的 MC38 细胞移植的小鼠中进一步评估了黑色素基疫苗的抗肿瘤疗效。与基于 IFA 的疫苗相比，黑色素基疫苗诱导 E.G7-OVA 肿瘤生长的主要抑制（p<0.001），但肿瘤最终从第 24 天开始复发。在 MC38 肿瘤模型中，未观察到肿瘤生长的显著抑制。在两种情况下，肿瘤逃逸似乎与肿瘤细胞抗原呈递的丧失有关（E.G7-OVA 模型中卵清蛋白表达的丧失；MC38 模型中 mAdpgk 的呈递不良），尽管 CTL 反应显示出效应记忆表型、高细胞毒性潜力和低程序性细胞死亡-1（PD1）表达。总之，合成黑色素可有效地用作佐剂，以增强针对亚单位疫苗抗原的 T 细胞反应，并在小鼠中优于经典的 IFA 和 TLR9 激动剂组合。
