Vaccine Development Laboratory, Department of Microbiology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil.
Department of Clinical Chemistry and Toxicology, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
Front Immunol. 2018 Aug 22;9:1914. doi: 10.3389/fimmu.2018.01914. eCollection 2018.
Immunotherapy has become an important ally in the fight against distinct types of cancer. However, the metabolic plasticity of the tumor environment frequently influences the efficacy of therapeutic procedures, including those based on immunological tools. In this scenario, immunometabolic adjuvants arise as an alternative toward the development of more efficient cancer therapies. Here we demonstrated that the combination of melatonin, a neuroimmunomodulator molecule, and an indoleamine 2,3-dioxygenase (IDO) inhibitor (1-methyl-DL-tryptophan, DL-1MT) improves the efficacy of an immunotherapy (gDE7) targeting human papillomavirus (HPV)-associated tumors. Melatonin or IDO inhibitors (D-1MT and DL-1MT) directly reduced proliferation, migration, adhesion and viability of a tumor cell line (TC-1), capable to express the HPV-16 E6 and E7 oncoproteins, but could not confer antitumor protection effects. Nonetheless, combination of gDE7 with melatonin or D-1MT or DL-1MT enhanced the antitumor protective immunity of gDE7-based vaccine in mice. Notably, expression of IDO1 in stromal cells and/or immune cells, but not in tumor cells, inhibited the antitumor effects of the gDE7, as demonstrated in IDO1-deficient mice. Finally, co-administration of gDE7, melatonin and DL-1MT further improved the protective antitumor effects and the numbers of circulating E7-specific CD8 T cells in mice previously transplanted with TC-1 cells. The unprecedented combination of melatonin and IDO inhibitors, as immunometabolic adjuvants, thus, represents a new and promising alternative for improving the efficacy of immunotherapeutic treatments of HPV-associated tumors.
免疫疗法已成为对抗多种癌症的重要手段。然而，肿瘤微环境的代谢可塑性经常影响治疗方法的疗效，包括基于免疫工具的治疗方法。在这种情况下，免疫代谢佐剂作为开发更有效的癌症治疗方法的替代方案出现。在这里，我们证明了褪黑素（一种神经免疫调节剂分子）和吲哚胺 2,3-双加氧酶（IDO）抑制剂（1-甲基-DL-色氨酸，DL-1MT）的组合可提高针对人乳头瘤病毒（HPV）相关肿瘤的免疫疗法（gDE7）的疗效。褪黑素或 IDO 抑制剂（D-1MT 和 DL-1MT）直接降低了能够表达 HPV-16 E6 和 E7 癌蛋白的肿瘤细胞系（TC-1）的增殖、迁移、黏附和活力，但不能赋予抗肿瘤保护作用。然而，gDE7 与褪黑素或 D-1MT 或 DL-1MT 的组合增强了 gDE7 疫苗在小鼠中的抗肿瘤保护免疫。值得注意的是，在基质细胞和/或免疫细胞中表达 IDO1，但不在肿瘤细胞中表达，抑制了 gDE7 的抗肿瘤作用，正如在 IDO1 缺陷型小鼠中所证明的那样。最后，gDE7、褪黑素和 DL-1MT 的共同给药进一步改善了 TC-1 细胞移植小鼠的保护性抗肿瘤作用和循环 E7 特异性 CD8 T 细胞的数量。褪黑素和 IDO 抑制剂作为免疫代谢佐剂的前所未有的组合，因此代表了改善 HPV 相关肿瘤免疫治疗疗效的新的有前途的替代方案。
