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Lactate secreted by cervical cancer cells modulates macrophage phenotype
Author(s) -
Stone Simone Cardozo,
Rossetti Renata Ariza Marques,
Alvarez Karla Lucia Fernandez,
Carvalho Jesus Paula,
Margarido Paulo Francisco Ramos,
Baracat Edmund Chada,
Tacla Maricy,
Boccardo Enrique,
Yokochi Kaori,
Lorenzi Noely Paula,
Lepique Ana Paula
Publication year - 2019
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.3a0718-274rr
Subject(s) - biology , immune system , lactate dehydrogenase , secretion , cancer cell , angiogenesis , lactate dehydrogenase a , tumor microenvironment , cancer research , phenotype , cervical cancer , glycolysis , cancer , immunology , medicine , endocrinology , metabolism , biochemistry , enzyme , gene , genetics
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, Mϕs, and dendritic cells. We and others have previously shown that Mϕs 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 Mϕ 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 Mϕs, promoting secretion of IL‐1β, IL‐10, IL‐6, and up‐regulation of hypoxia induced factor‐1α expression, and down‐regulation of p65‐NFκB phosphorylation in Mϕs. We also showed that Mϕs 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 Mϕs, promoting a suppressive phenotype.