bims-stacyt 2019-03-03 papers

J Leukoc Biol. 2019 Feb 27.

Lactate secreted by cervical cancer cells modulates macrophage phenotype.

Simone Cardozo Stone, Renata Ariza Marques Rossetti, Karla Lucia Fernandez Alvarez, Jesus Paula Carvalho, Paulo Francisco Ramos Margarido, Edmund Chada Baracat, Maricy Tacla, Enrique Boccardo, Kaori Yokochi, Noely Paula Lorenzi, Ana Paula Lepique.

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.

Keywords: cervical cancer; human papillomavirus; lactate; monocarboxylate transporters; tumor microenvironment

DOI: https://doi.org/10.1002/JLB.3A0718-274RR

Sleep Breath. 2019 Mar 01.

Mechanisms of vascular endothelial cell injury in response to intermittent and/or continuous hypoxia exposure and protective effects of anti-inflammatory and anti-oxidant agents.

Fan Xiao, Xin Li, Juan Wang, Jie Cao.

BACKGROUND: Hypoxia induces vascular endothelial injuries; however, the mechanisms involved and effects of interventions remain unclear.OBJECTIVE: Investigate the inflammatory response and oxidative stress in co-cultured neutrophils and vascular endothelial cells, apoptotic changes in endothelial cells, and effects of the antioxidant, Tempol, or the NF-êB inflammatory channel blocker, pyrrolidine dithiocarbamate (PDTC), upon endothelial cells under conditions of intermittent and/or continuous hypoxic exposure.
METHODS: Polymorphonuclear neutrophils co-cultured with human umbilical vein endothelial cells were subjected to the following conditions: intermittent normoxia (IN), intermittent hypoxia (IH), continuous hypoxia (CH), intermittent with continuous hypoxia (OS), OS+Tempol (OS+T), or OS+PDTC (OS+P) for 2, 5, or 8 h. Inflammatory factors, TNF-α and IL-6, the adhesion molecule, ICAM-1, CAT activity, and MDA concentrations in supernatants from the co-culture as well as pro- (Bak) and anti- (Bcl-xl) apoptotic gene expression levels in the endothelial cells were determined.
RESULTS: Inflammatory factors, adhesion molecules, oxidative stress, and apoptosis genes in all groups showed significant, time-dependent increases as compared with the IN group. TNF-α, IL-6, ICAM-1, and MDA levels in the OS group were increased, while CAT was decreased as compared with that observed in the IH, CH, OS+T, and OS+P groups. Bcl-x1 expression and Bcl-x1/BAK ratios were decreased and BAX increased in the OS versus IH, CH, OS+T, or OS+P groups. Both pro- and anti-apoptotic proteins showed time-dependent increases, while the Bcl-x1/BAK ratio decreased over these times. Tempol and PDTC partially prevented these effects.
CONCLUSION: Inflammation, oxidative stress, and apoptosis are all involved in vascular endothelial injury induced by OS. Anti-inflammatory and anti-oxidative interventions can partially improve effects of OS.

Keywords: Apoptosis; Hypoxia; Inflammation; Interaction; Neutrophils; Oxidative stress; Vascular endothelial cells

DOI: https://doi.org/10.1007/s11325-019-01803-9

Nat Rev Immunol. 2019 Feb 28.

Metabolic interventions in the immune response to cancer.

David O'Sullivan, David E Sanin, Edward J Pearce, Erika L Pearce.

At the centre of the therapeutic dilemma posed by cancer is the question of how to develop more effective treatments that discriminate between normal and cancerous tissues. Decades of research have shown us that universally applicable principles are rare, but two well-accepted concepts have emerged: first, that malignant transformation goes hand in hand with distinct changes in cellular metabolism; second, that the immune system is critical for tumour control and clearance. Unifying our understanding of tumour metabolism with immune cell function may prove to be a powerful approach in the development of more effective cancer therapies. Here, we explore how nutrient availability in the tumour microenvironment shapes immune responses and identify areas of intervention to modulate the metabolic constraints placed on immune cells in this setting.

DOI: https://doi.org/10.1038/s41577-019-0140-9