Lactate secreted by cervical cancer cells modulates macrophage phenotype

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Stone, Simone Cardozo ^[1] ; Marques Rossetti, Renata Ariza ^[1] ; Fernandez Alvarez, Karla Lucia ^[1] ; Carvalho, Jesus Paula ^[2] ; Ramos Margarido, Paulo Francisco ^[3] ; Baracat, Edmund Chada ^{[3, 2, 4]} ; Tacla, Maricy ^[4] ; Boccardo, Enrique ^[5] ; Yokochi, Kaori ^[3] ; Lorenzi, Noely Paula ^{[3, 4]} ; Lepique, Ana Paula ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Immunol, Ave Prof Lineu Prestes de Oliveira 1730, Room 136, Sao Paulo, SP - Brazil

^[2] Inst Canc Estado Sao Paulo, Dept Oncol Gynecol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Univ Hosp, Div Obstet & Gynecol, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Fac Med, Hosp Clin, Dept Gynecol, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Inst Ciencias Biomed, Dept Microbiol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Leukocyte Biology; v. 105, n. 5, p. 1041-1054, MAY 2019.
• Citações Web of Science: 3

Resumo

Cervical cancer continues to be a public health problem in developing countries. Previous studies have shown that cervical cancer cells display markers of aerobic glycolysis, indicating that these tumors are likely to secrete lactate. Mostly, lactate is recognized as a molecule capable of suppressing immune responses, through inhibition of T cells, M phi s, and dendritic cells. We and others have previously shown that M phi s are frequent cells infiltrating cervical cancers with the ability to inhibit antitumor immune responses and promote tumor growth through angiogenesis. Here, we have tested the hypothesis that lactate, secreted by cervical cancer cells, can modulate M phi phenotype. First, we showed higher lactate plasma concentrations in patients with increasing cervical lesion grades, with maximum concentration in the plasma of cancer patients, which supported our hypothesis. We then inhibited lactate production in tumor cell spheroids established from cervical cancer derived cell lines, using the lactate dehydrogenase inhibitor, oxamate, prior to co-culture with monocytes. Lactate mediated part of the crosstalk between tumor cells and M phi s, promoting secretion of IL-1, IL-10, IL-6, and up-regulation of hypoxia induced factor-1 expression, and down-regulation of p65-NFB phosphorylation in M phi s. We also showed that M phi s from co-cultures treated with oxamate were better inducers of T cell activation. Of note, experiments performed with inhibition of the monocarboxylate transporters rendered similar results. Our data confirms the hypothesis that lactate, secreted by cervical tumor cells, influences the phenotype of tumor M phi s, promoting a suppressive phenotype. (AU)

• Processo FAPESP: 08/57889-1 - Instituto de Ciência e Tecnologia para o Estudo das Doenças Associadas ao Papilomavírus
• Beneficiário: Luisa Lina Villa
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 14/19326-6 - Microambiente tumoral, inflamação e imunomodulação: possibilidades terapêuticas e marcadores de prognóstico
• Beneficiário: Ana Paula Lepique
• Modalidade de apoio: Auxílio à Pesquisa - Regular