Tumor-derived lactic acid modulates dendritic cell activation and antigen expression

Gottfried, Eva; Kunz-Schughart, Leoni A.; Ebner, Stephanie; Mueller‐Klieser, Wolfgang; Hoves, Sabine; Andreesen, Reinhard; Mackensen, Andréas; Kreutz, Marina

doi:10.1182/blood-2005-05-1795

Cited by 581 publications

(442 citation statements)

References 48 publications

Supporting

Mentioning

420

Contrasting

Unclassified

Order By: Relevance

“…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). These studies have suggested a role for lactate/extracellular pH on tumor growth through inhibition of immune surveillance.…”

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

627

473

View full text Add to dashboard Cite

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.

show abstract

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

627

473

View full text Add to dashboard Cite

show abstract

“…Indeed, the acquired acidic phenotype enables cancer cells to suppress the anti-cancer activity of immune cells promoting the secretion of chemokines to enhance T-regulatory recruitment or producing immunosuppressive cytokines [83]. Several studies have shown that acidic pH e inhibits T-cell proliferation [84], dendritic cell maturation [85], cytotoxic T lymphocyte activity (CTLs) [86], lymphokine-activated killer cells [87], and natural killer (NK) activity and viability [88]. Furthermore, lowering pH e to 6.5 has been reported to lead to a loss of function of human and murine tumor-infiltrating T lymphocytes consisting in a significant impairment of cytolytic activity, cytokine secretion, and reduction of T-cell receptor and interleukin-2 α-chain receptor expression [89].…”

Section: Acidity Favours Escaping From Immune Surveillancementioning

confidence: 99%

The acidic microenvironment as a possible niche of dormant tumor cells

Peppicelli

Andreucci

Ruzzolini

et al. 2017

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

“…Accordingly, Gao and coauthors described elevated levels of LDH and lactate in the serum of RCC patients. 20 We have demonstrated that lactate, the end product of glycolysis, inhibits the maturation of human dendritic cells 22 and impairs the activation and proliferation of CD8 þ T cells. Furthermore, high lactate concentration leads to induction of apoptosis in CD8 þ T cells.…”

Section: Tumor Immunologymentioning

confidence: 99%

“…17 Proteomic analysis of tumor tissues 18,19 and metabolic profiling of serum samples revealed a ''Warburg phenotype'' in RCC with increased levels of glycolytic enzymes in tumor lesions and higher levels of the glycolysis end product lactate in the serum of RCC patients. 20 We have demonstrated that lactate can suppress effector functions of human cytotoxic T cells 21 as well as maturation of dendritic cells 22 in vitro. Since RCC represents a highly immunogenic tumor the glycolytic switch of RCC cells might influence the antitumor immune response in tumor patients and the high glucose turnover by tumor cells could alter T cell activation.…”

mentioning

confidence: 99%

Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8⁺ T‐cell infiltration in the tumor

Singer

Kastenberger

Gottfried³

et al. 2011

Intl Journal of Cancer

Self Cite

142

View full text Add to dashboard Cite

Many tumor cells are characterized by a dysregulated glucose metabolism associated with increased glycolysis in the presence of oxygen (''Warburg Effect''). Here, we analyzed for the first time a possible link between glucose metabolism and immune cell infiltration in renal cell carcinoma (RCC). RCC specimens revealed a highly significant increase in the expression of lactate dehydrogenase A (LDHA) and glucose-transporter 1 (GLUT-1) compared to the corresponding normal kidney tissue on mRNA level. Accordingly, tumor cell lines of different origin such as RCC, melanoma and hepatocellular carcinoma strongly expressed LDHA and GLUT-1 compared to their nonmalignant counterparts. In line with this finding, tumor cells secreted high amounts of lactate. High expression of GLUT-1 and LDH5, a tetramer of 4 LDHA subunits, was confirmed by tissue microarray analysis of 249 RCC specimens. Overall, 55/79 (69.6%) and 46/71 (64.7%) cases of clear cell carcinoma showed a constitutive, but heterogeneous expression of GLUT-1 and LDH5, respectively. The number of CD3 1 , CD8 1 and FOXP3 1 T cells was significantly elevated in RCC lesions compared to normal kidney epithelium, but effector molecules such as granzyme B and perforin were decreased in tumor infiltrating T cells. Of interest, further analysis revealed an inverse correlation between GLUT-1 expression and the number of CD8 1 T cells in RCC lesions. Together, our data suggest that an accelerated glucose metabolism in RCC tissue is associated with a low infiltration of CD8 1 effector T cells. Targeting the glucose metabolism may represent an interesting tool to improve the efficacy of specific immunotherapeutic approaches in RCC.Renal cell carcinoma (RCC) constitutes 2-3% of all malignant tumors in adults. It is a very heterogeneous malignancy, which is subdivided in different histological subtypes. The most common type of RCC is clear cell carcinoma with an incidence of 75% whereas the papillary (10-15%) and the chromophobe subtypes (5%) are less frequent. 1,2 Clear cell carcinoma arises from cells of the proximal tubule and is characterized by a clear cytoplasm, which stores glycogen. It is associated with a large number of gene mutations most notably in the von Hippel Lindau (VHL) gene. 3,4 The VHL protein is crucially involved in the regulation of the hypoxia inducible transcription factor HIF1. In the absence of VHL, HIF is stabilized and induces the expression of proteins that are involved in angiogenesis and glucose metabolism, e.g., vascular endothelial growth factor (VEGF), erythropoietin and glucose-transporter 1 (GLUT-1). 5,6 Overexpression of GLUT-1 has been described in different malignancies 7-9 and polymorphisms of GLUT-1 seems to be associated with clear cell carcinoma. 10 Beside HIF stabilization through loss of the tumor suppressor gene VHL or hypoxia, oncogenic transformation, caused by loss of p53, 11,12 mutation of KRAS/BRAF 13 or c-myc overexpression 14 reduces respiration accompanied by an upregulation of glycolytic enzymes such as lactate dehydrogena...

show abstract

Tumor-derived lactic acid modulates dendritic cell activation and antigen expression

Cited by 581 publications

References 48 publications

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

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

The acidic microenvironment as a possible niche of dormant tumor cells

Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8⁺ T‐cell infiltration in the tumor

Contact Info

Product

Resources

About

Tumor-derived lactic acid modulates dendritic cell activation and antigen expression

Cited by 581 publications

References 48 publications

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

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

The acidic microenvironment as a possible niche of dormant tumor cells

Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8+ T‐cell infiltration in the tumor

Contact Info

Product

Resources

About

Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8⁺ T‐cell infiltration in the tumor