Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c‐Jun activation

Mendler, Anna N.; Hu, Bin; Prinz, Petra U.; Kreutz, Marina; Gottfried, Eva; Noeßner, Elfriede

doi:10.1002/ijc.26410

Cited by 242 publications

(201 citation statements)

References 28 publications

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“…Among the natural ligands of PPAR, various eicosanoids, such as leucotriene B4, are generated during inflammatory responses [20,21]. In addition to these effects of ligand-bound PPAR on NF-B and c-jun, it has also been reported that ligand-free PPAR may inhibit the phosphorylation of p38 [22], a kinase that also promotes IFN transcription downstream of TCR stimulation [23]. Thus, we analyzed the in vitro response of human V9V2 T cells stimulated with a PPAR agonist, LY171883.…”

Section: Resultsmentioning

confidence: 99%

The PPARα pathway in Vγ9Vδ2 T cell anergy

Poupot

Boissard

Bétous

et al. 2014

Cellular and Molecular Biology Letters

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Phosphoantigens (PAgs) activate V9V2 T lymphocytes, inducing their potent and rapid response in vitro and in vivo. However, humans and nonhuman primates that receive repeated injections of PAgs progressively lose their V9V2 T cell response to them. To elucidate the molecular mechanisms of this in vivo desensitization, we analyzed the transcriptome of circulating V9V2 T cells from macaques injected with PAg. We showed that three PAg injections induced the activation of the PPAR pathway in V9V2 T cells. Thus, we analyzed the in vitro response of V9V2 T cells stimulated with a PPAR agonist. We demonstrated that in vitro PPAR pathway activation led to the inhibition of the BrHPP-induced activation and proliferation of human V9V2 T cells. Since the PPAR pathway is involved in the antigen-selective desensitization of human V9V2 T cells, the use of PPAR inhibitors could enhance cancer immunotherapy based on V9V2 T cells.

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Section: Resultsmentioning

confidence: 99%

The PPARα pathway in Vγ9Vδ2 T cell anergy

Poupot

Boissard

Bétous

et al. 2014

Cellular and Molecular Biology Letters

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“…The increased production of lactate has been correlated to increased metastatic potential (24)(25)(26). In terms of lactate's impact on immune cells, recent studies have shown that lactate suppresses the function of tumor-specific T cells, inhibits tumor specific cytotoxic T cell activity (27), and induces defect in signal transduction (28). Lactate/low pH also alters the Ag-presenting ability of dendritic cells (29), inhibits cytotoxic activity (30), and promotes IL-23/IL-17 proinflammatory pathway (31).…”

Section: Discussionmentioning

confidence: 99%

Tumor-Derived Lactate Modifies Antitumor Immune Response: Effect on Myeloid-Derived Suppressor Cells and NK Cells

Husain

Huang

Seth

et al. 2013

The Journal of Immunology

630

473

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In this study, we explore the hypothesis that enhanced production of lactate by tumor cells, because of high glycolytic activity, results in inhibition of host immune response to tumor cells. Lactate dehydrogenase-A (LDH-A), responsible for conversion of pyruvate to lactate, is highly expressed in tumor cells. Lentiviral vector–mediated LDH-A short hairpin RNA knockdown Pan02 pancreatic cancer cells injected in C57BL/6 mice developed smaller tumors than mice injected with Pan02 cells. A decrease occurred in the frequency of myeloid-derived suppressor cells (MDSCs) in the spleens of mice carrying LDH-A–depleted tumors. NK cells from LDH-A–depleted tumors had improved cytolytic function. Exogenous lactate increased the frequency of MDSCs generated from mouse bone marrow cells with GM-CSF and IL-6 in vitro. Lactate pretreatment of NK cells in vitro inhibited cytolytic function of both human and mouse NK cells. This reduction of NK cytotoxic activity was accompanied by lower expression of perforin and granzyme in NK cells. The expression of NKp46 was decreased in lactate-treated NK cells. These studies strongly suggest that tumor-derived lactate inhibits NK cell function via direct inhibition of cytolytic function as well as indirectly by increasing the numbers of MDSCs that inhibit NK cytotoxicity. Depletion of glucose levels using a ketogenic diet to lower lactate production by glycolytic tumors resulted in smaller tumors, decreased MDSC frequency, and improved antitumor immune response. These studies provide evidence for an immunosuppressive role of tumor-derived lactate in inhibiting innate immune response against developing tumors via regulation of MDSC and NK cell activity.

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“…Indeed, the inflammatory response is often necessary for tumor progression, and elevated numbers of inflammatory cells, such as tumor-associated macrophages, connote poor prognosis (41). Furthermore, lactate in the tumor cell milieu impairs the adaptive immune response, disabling immune surveillance (43)(44)(45)(46). Thus, lactate also appears to promote tumorigenesis via non-tumor cell-mediated effects on the inflammatory and immune responses.…”

Section: Figurementioning

confidence: 99%

Targeting lactate metabolism for cancer therapeutics

Doherty¹,

Cleveland²

2013

J. Clin. Invest.

920

876

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Lactate, once considered a waste product of glycolysis, has emerged as a critical regulator of cancer development, maintenance, and metastasis. Indeed, tumor lactate levels correlate with increased metastasis, tumor recurrence, and poor outcome. Lactate mediates cancer cell intrinsic effects on metabolism and has additional non-tumor cell autonomous effects that drive tumorigenesis. Tumor cells can metabolize lactate as an energy source and shuttle lactate to neighboring cancer cells, adjacent stroma, and vascular endothelial cells, which induces metabolic reprogramming. Lactate also plays roles in promoting tumor inflammation and in functioning as a signaling molecule that stimulates tumor angiogenesis. Here we review the mechanisms of lactate production and transport and highlight emerging evidence indicating that targeting lactate metabolism is a promising approach for cancer therapeutics.

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Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c‐Jun activation

Cited by 242 publications

References 28 publications

The PPARα pathway in Vγ9Vδ2 T cell anergy

The PPARα pathway in Vγ9Vδ2 T cell anergy

Tumor-Derived Lactate Modifies Antitumor Immune Response: Effect on Myeloid-Derived Suppressor Cells and NK Cells

Targeting lactate metabolism for cancer therapeutics

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