The Combined Use of Melatonin and an Indoleamine 2,3-Dioxygenase-1 Inhibitor Enhances Vaccine-Induced Protective Cellular Immunity to HPV16-Associated Tumors

Autor(es):Mostrar menos -

Moreno, Ana C. R. ^[1] ; Porchia, Bruna F. M. M. ^[1] ; Pagni, Roberta L. ^[1] ; Souza, Patricia da Cruz ^[1] ; Pegoraro, Rafael ^[1] ; Rodrigues, Karine B. ^[1] ; Barros, Tacita B. ^{[1, 2]} ; de Melo Moraes Aps, Luana R. ^[1] ; de Araujo, Eliseu F. ^[3] ; Calich, Vera L. G. ^[3] ; de Souza Ferreira, Luis C. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Biomed Sci Inst, Dept Microbiol, Vaccine Dev Lab, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin Chem & Toxicol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Biomed Sci Inst, Dept Immunol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN IMMUNOLOGY; v. 9, AUG 22 2018.
• Citações Web of Science: 0

Resumo

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. (AU)

• Processo FAPESP: 16/23189-0 - Modulação das respostas Treg/Th17 por ligantes de AhR na busca de procedimento imunoterápico para a paracoccidioidomicose pulmonar
• Beneficiário: Vera Lucia Garcia Calich
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/20917-0 - Imunoterapia envolvendo a oncoproteína E7 e a glicoproteína D (gD) do vírus herpes em formulações vacinais voltadas para o controle de tumores associados a papillomavirus
• Beneficiário: Bruna Felício Milazzotto Maldonado Porchia Ribeiro
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/00708-1 - Indoleamina 2,3 dioxigenase (IDO) na biologia de tumores associados aos papilomavírus humano (HPV): efeitos neoadjuvantes na imunoterapia tumoral
• Beneficiário: Ana Carolina Ramos Moreno
• Modalidade de apoio: Bolsas no Brasil - Jovens Pesquisadores
• Processo FAPESP: 15/16505-0 - Indoleamina 2,3 dioxigenase (IDO) na biologia de tumores associados aos papilomavírus humano (HPV): efeitos neoadjuvantes na imunoterapia tumoral
• Beneficiário: Ana Carolina Ramos Moreno
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 13/15360-2 - Novas fronteiras terapêuticas contra tumores causados pelo vírus do papiloma humano (HPV): avaliação experimental da associação da quimioterapia com estratégias vacinais
• Beneficiário: Luana Raposo de Melo Moraes Aps
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 17/25544-4 - Papel da indoleamina 2,3 dioxigenase (IDO) na oncogênese e imunossupressão de tumores associados ao papilomavírus humano (HPV)
• Beneficiário: Roberta Liberato Pagni
• Modalidade de apoio: Bolsas no Brasil - Mestrado