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Journal ArticleDOI

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

01 Aug 2013-Journal of Immunology (J Immunol)-Vol. 191, Iss: 3, pp 1486-1495
TL;DR: Evidence is provided for an immunosuppressive role of tumor-derived lactate in inhibiting innate immune response against developing tumors via regulation of MDSC and NK cell activity.
Abstract: 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.
Citations
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Journal ArticleDOI
TL;DR: It is shown that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells, and is a potent inhibitor of function and survival of T andNK cells leading to tumor immune escape.

948 citations


Cites background from "Tumor-Derived Lactate Modifies Anti..."

  • ..., 2008) and increases the number of MDSCs in the spleens of mice carrying LDHA-expressing tumors (Husain et al., 2013)....

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  • ...Furthermore, Husain et al. reported reduced numbers of myeloid-derived suppressor cells (MDSCs) in the spleens of mice carrying Ldha-depleted tumors (Husain et al., 2013)....

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  • ...Since tumors expressing high levels of Ldha modulate immune cell infiltration and differentiation in the spleens of tumor-bearing mice (Husain et al., 2013), we analyzed myeloid and lymphoid cells in the blood and spleen of tumor-bearing C57BL/6 mice....

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  • ...reported reduced numbers of myeloid-derived suppressor cells (MDSCs) in the spleens of mice carrying Ldha-depleted tumors (Husain et al., 2013)....

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  • ...Since tumors expressing high levels of Ldha modulate immune cell infiltration and differentiation in the spleens of tumor-bearing mice (Husain et al., 2013), we analyzed myeloid and lymphoid cells in the blood and spleen of tumor-bearing C57BL/6 mice....

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Journal ArticleDOI
TL;DR: The focus of this review is on the remodeling of the tumor microenvironment that leads to pathophysiologic interactions that are influenced and shaped by metabolism.

552 citations

Journal ArticleDOI
TL;DR: How the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, and pancreatic and ovarian cancer, is discussed, and how scientific advances may help overcome these hurdles are discussed.

453 citations


Cites background from "Tumor-Derived Lactate Modifies Anti..."

  • ...The presence of excess lactate can also enhance the functions of immunosuppressive cells, such as myeloid subsets, and polarize macrophages to an immunosuppressive phenotype (Colegio et al., 2014; Husain et al., 2013)....

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Journal ArticleDOI
TL;DR: The goal of this review is to expose that lactate is not only a secondary product of cellular metabolic waste of tumor cells, but also a key molecule involved in carcinogenesis as well as in tumor immune evasion.
Abstract: Tumor cells must generate sufficient ATP and biosynthetic precursors in order to maintain cell proliferation requirements. Otto Warburg showed that tumor cells uptake high amounts of glucose producing large volumes of lactate even in the presence of oxygen, this process is known as "Warburg effect or aerobic glycolysis." As a consequence of such amounts of lactate there is an acidification of the extracellular pH in tumor microenvironment, ranging between 6.0 and 6.5. This acidosis favors processes such as metastasis, angiogenesis and more importantly, immunosuppression, which has been associated to a worse clinical prognosis. Thus, lactate should be thought as an important oncometabolite in the metabolic reprogramming of cancer. In this review, we summarized the role of lactate in regulating metabolic microenvironment of cancer and discuss its relevance in the up-regulation of the enzymes lactate dehydrogenase (LDH) and monocarboxilate transporters (MCTs) in tumors. The goal of this review is to expose that lactate is not only a secondary product of cellular metabolic waste of tumor cells, but also a key molecule involved in carcinogenesis as well as in tumor immune evasion. Finally, the possible targeting of lactate production in cancer treatment is discussed.

430 citations

Journal ArticleDOI
TL;DR: It is posited that in carcinogenesis, aberrant cell signaling due to exaggerated and continually high lactate levels yields an inappropriate positive feedback loop that increases glucose uptake, glycolysis, lactate production and release, decreases mitochondrial function and clearance and upregulates glyCOlytic enzyme and monocarboxylate transporter expression thereby supporting angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism.
Abstract: Herein, we use lessons learned in exercise physiology and metabolism to propose that augmented lactate production ('lactagenesis'), initiated by gene mutations, is the reason and purpose of the Warburg Effect and that dysregulated lactate metabolism and signaling are the key elements in carcinogenesis. Lactate-producing ('lactagenic') cancer cells are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Otto Warburg 93 years ago, which still remains unexplained. After a hiatus of several decades, interest in lactate as a player in cancer has been renewed. In normal physiology, lactate, the obligatory product of glycolysis, is an important metabolic fuel energy source, the most important gluconeogenic precursor, and a signaling molecule (i.e. a 'lactormone') with major regulatory properties. In lactagenic cancers, oncogenes and tumor suppressor mutations behave in a highly orchestrated manner, apparently with the purpose of increasing glucose utilization for lactagenesis purposes and lactate exchange between, within and among cells. Five main steps are identified (i) increased glucose uptake, (ii) increased glycolytic enzyme expression and activity, (iii) decreased mitochondrial function, (iv) increased lactate production, accumulation and release and (v) upregulation of monocarboxylate transporters MTC1 and MCT4 for lactate exchange. Lactate is probably the only metabolic compound involved and necessary in all main sequela for carcinogenesis, specifically: angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism. We hypothesize that lactagenesis for carcinogenesis is the explanation and purpose of the Warburg Effect. Accordingly, therapies to limit lactate exchange and signaling within and among cancer cells should be priorities for discovery.

406 citations


Cites background from "Tumor-Derived Lactate Modifies Anti..."

  • ...Lactate also inhibits natural killer cell function directly by inhibiting cytolytic function and indirectly by increasing the numbers of myeloid-derived suppressor cells that inhibit natural killer cytotoxicity (176)....

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References
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Journal ArticleDOI
TL;DR: The origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit are discussed.
Abstract: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.

5,811 citations

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TL;DR: The historical and experimental basis of cancer immunoediting is summarized and its dual roles in promoting host protection against cancer and facilitating tumor escape from immune destruction are discussed.
Abstract: The concept that the immune system can recognize and destroy nascent transformed cells was originally embodied in the cancer immunosurveillance hypothesis of Burnet and Thomas. This hypothesis was abandoned shortly afterwards because of the absence of strong experimental evidence supporting the concept. New data, however, clearly show the existence of cancer immunosurveillance and also indicate that it may function as a component of a more general process of cancer immunoediting. This process is responsible for both eliminating tumors and sculpting the immunogenic phenotypes of tumors that eventually form in immunocompetent hosts. In this review, we will summarize the historical and experimental basis of cancer immunoediting and discuss its dual roles in promoting host protection against cancer and facilitating tumor escape from immune destruction.

4,586 citations

Journal ArticleDOI
TL;DR: In this article, the authors propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions, which leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity.
Abstract: If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.

4,361 citations

Journal ArticleDOI
TL;DR: This review examines the idea that several core fluxes, including aerobic glycolysis, de novo lipid biosynthesis, and glutamine-dependent anaplerosis, form a stereotyped platform supporting proliferation of diverse cell types and regulates regulation of these fluxes by cellular mediators of signal transduction and gene expression.

3,526 citations

Journal Article
TL;DR: Current knowledge of blood flow and perfusion-related parameters, which usually go hand in hand and in turn define the cellular metabolic microenvironment of human malignancies, are summarized for predicting the acute and/or long-term response of tumors to therapy.
Abstract: The objective of this review article is to summarize current knowledge of blood flow and perfusion-related parameters, which usually go hand in hand and in turn define the cellular metabolic microenvironment of human malignancies. A compilation of available data from the literature on blood flow, oxygen and nutrient supply, and tissue oxygen and pH distribution in human tumors is presented. Whenever possible, data obtained for human tumors are compared with the respective parameters in normal tissues, isotransplanted or spontaneous rodent tumors, and xenografted human tumors. Although data on human tumors in situ are scarce and there may be significant errors associated with the techniques used for measurements, experimental evidence is provided for the existence of a compromised and anisotropic blood supply to many tumors. As a result, O2-depleted areas develop in human malignancies which coincide with nutrient and energy deprivation and with a hostile metabolic microenvironment (e.g., existence of severe tissue acidosis). Significant variations in these relevant parameters must be expected between different locations within the same tumor, at the same location at different times, and between individual tumors of the same grading and staging. Furthermore, this synopsis will attempt to identify relevant pathophysiological parameters and other related areas future research of which might be most beneficial for designing individually tailored treatment protocols with the goal of predicting the acute and/or long-term response of tumors to therapy.

3,379 citations

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