The Combined Use of Melatonin and an Indoleamine 2,3-Dioxygenase-1 Inhibitor Enhances Vaccine-Induced Protective Cellular Immunity to HPV16-Associated Tumors.
The Combined Use of Melatonin and an Indoleamine 2,3-Dioxygenase-1 Inhibitor Enhances Vaccine-Induced Protective Cellular Immunity to HPV16-Associated Tumors.
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DOI：
10.3389/fimmu.2018.01914
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发表时间：
2018
影响因子：
7.3
通讯作者：
Ferreira LCS
中科院分区：
文献类型：
--
作者：
Moreno ACR;Porchia BFMM;Pagni RL;Souza PDC;Pegoraro R;Rodrigues KB;Barros TB;Aps LRMM;de Araújo EF;Calich VLG;Ferreira LCS
免疫疗法已经成为对抗不同类型癌症的重要盟友。然而，肿瘤环境的代谢可塑性经常影响治疗程序的有效性，包括那些基于免疫工具的治疗程序。在这种情况下，免疫代谢佐剂作为开发更有效的癌症治疗的替代方案而出现。在这里，我们证明了褪黑素，一种神经免疫调节分子和吲哚胺2,3-双加氧酶（IDO）抑制剂（1-甲基- dl -色氨酸，DL-1MT）的组合可以提高针对人乳头瘤病毒（HPV）相关肿瘤的免疫治疗（gDE7）的疗效。褪黑素或IDO抑制剂（D-1MT和DL-1MT）直接降低肿瘤细胞系（TC-1）的增殖、迁移、粘附和活力，能够表达HPV-16 E6和E7癌蛋白，但不能赋予体内抗肿瘤保护作用。然而，gDE7与褪黑素或D-1MT或DL-1MT联合使用可增强gDE7疫苗在小鼠体内的抗肿瘤保护免疫。值得注意的是，在基质细胞和/或免疫细胞中，而不是在肿瘤细胞中，IDO1的表达抑制了gDE7的抗肿瘤作用，这在IDO1缺陷小鼠中得到了证实。最后，gDE7、褪黑素和DL-1MT联合使用进一步提高了先前移植TC-1细胞的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。因此，褪黑激素和IDO抑制剂作为免疫代谢佐剂的前所未有的组合，代表了一种新的和有希望的替代方法，可以提高hpv相关肿瘤的免疫治疗效果。
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 in vivo 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.
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影响因子：
8.8
作者：
Holmgaard RB;Zamarin D;Li Y;Gasmi B;Munn DH;Allison JP;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
11.2
作者：
Kang TH;Mao CP;Lee SY;Chen A;Lee JH;Kim TW;Alvarez RD;Roden RB;Pardoll D;Hung CF;Wu TC
通讯作者：
Wu TC
影响因子：
8.8
作者：
Jenkins RW;Barbie DA;Flaherty KT
通讯作者：
Flaherty KT
影响因子：
10.3
作者：
Ordonez, Raquel;Carbajo-Pescador, Sara;Mauriz, Jose L.
通讯作者：
Mauriz, Jose L.
影响因子：
11.2
作者：
Hou, De-Yan;Muller, Alexander J.;Munn, David H.
通讯作者：
Munn, David H.