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Year : 2017  |  Volume : 13  |  Issue : 3  |  Page : 406-411

Lactate – A new frontier in the immunology and therapy of prostate cancer

Department of Medical Oncology and Radiotherapy, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

Date of Web Publication31-Aug-2017

Correspondence Address:
Iuliana Nenu
Department of Medical Oncology and Radiotherapy, No. 34-36, Republicii Street, Cluj-Napoca 400015
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.163692

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 > Abstract 

Prostate cancer, one of the most common male malignancies with an increasing incidence in the recent years, requires the development of new methods of treatment. One of the most debated subjects is the tumor-associated macrophages (TAM). Although, the pathophysiological mechanisms are still a subject of intense research, TAM acts as procarcinogenic factors. It was also demonstrated that hypoxia-inducible factor 1 (HIF1) induces the expression of TAM genes involved in prostate carcinogenesis. Furthermore, it should be noted that the stromal extracellular lactate, the result of tumoral glycolysis process is one of the HIF1 activators. In addition, lactate inhibits the differentiation of monocytes and dendritic cells and also induces the inactivation of the cytotoxic T-lymphocytes. Through an analysis of recent studies, we conclude that lactate is a vital component of several ways of modulating the immune response at the stromal prostatic adenocarcinoma including TAM activation and cytotoxic T lymphocytes immunosuppression. Our review focuses on the impact of lactate on prostatic adenocarcinoma progression in terms of its immunology, and how this influences the therapy of this condition and the clinical outcome.

Keywords: Cytotoxic T lymphocytes, lactate, prostate cancer, tumor-associated macrophages

How to cite this article:
Nenu I, Gafencu GA, Popescu T, Kacso G. Lactate – A new frontier in the immunology and therapy of prostate cancer. J Can Res Ther 2017;13:406-11

How to cite this URL:
Nenu I, Gafencu GA, Popescu T, Kacso G. Lactate – A new frontier in the immunology and therapy of prostate cancer. J Can Res Ther [serial online] 2017 [cited 2023 Jan 27];13:406-11. Available from: https://www.cancerjournal.net/text.asp?2017/13/3/406/163692

 > Introduction Top

Prostate adenocarcinoma is the most common cancer in men, and its incidence is increasing despite the existing screening programs.[1] Although surgery and radiotherapy have improved the overall survival, patients still present tumor relapses, many with castration-resistant forms. Thus, the prostate cancer biology is intensively studied in order to find the gaps and to develop new oncological methods of treatment accordingly.

The development and growth of the prostate tumor have been attributed to both its malignant cells and their heterogeneous supportive stroma, to which they intensively communicate through different metabolic reactions.[2] As this stroma is further composed of nonmalignant cells and extracellular matrix, prostate cancer biology could be divided into two major parts: One that implies the study of metabolic pathways in the malignant cell and the other that accounts the interactions between these cells and the nonmalignant ones. Nevertheless, few data describe this intriguing cellular communication.

Chronic inflammation, one of the “hallmarks of cancer,” it is now accepted as a cause of prostate cancer.[3] Recent studies are focused on the interaction between the cancerous cells and the immune cells from the tumoral microenvironment. It is generally accepted that are a subset of macrophages known as tumor-associated macrophages (TAM) that resemble the M2 phenotype.[4] Although TAM's act as pro-carcinogenic factors, their mechanisms of action are still under intense research. Moreover, in the process of carcinogenesis, immune evasion plays an important role. Lactate has been proven to be an agent that enhances the survival of the regulatory T lymphocytes (Treg) cells and diminishes the production of cytotoxic cytokines produced by CD8+ T-cells and also, hampers the differentiation of dendritic and natural killer cells.[5] One major feature of solid tumors is the presence of fluctuating oxygen levels with alternations between normoxic and hypoxic conditions. The key mediator of hypoxia consequences is the hypoxia-inducible factor (HIF), which induces the transcription of vascular endothelial growth factor (VEGF) in TAM.[6] Very recently, it was demonstrated that one activating factor of an HIF-1 alpha complex (the HIF-1α) is the tumor product of glycolysis, the extracellular lactic acid.[7]

Although, lactate interacts with a heterogeneous population of cells from the tumoral microenvironment, our review focuses on interaction between lactate and the immune cells that reside within the prostate tumor and the impact that has on the clinical outcome, radiotherapy and the chemotherapeutic agents.

 > Metabolic Changes Top

The cancer cells metabolism, mostly in solid neoplasms, here counting the prostate carcinoma, is also characterized by a process called aerobic glycolysis, initially described by Warburg,[8] which produces great amount of lactate even in the presence of patent oxygenation. Lactate biology in the terms of oncological research field was not put into the light for many years. However, recently, it was discovered the metabolic shift of the lactic acid toward tumorigenesis. It was found that lactate promotes cancer cells survival, invasion, metastasis, and angiogenesis; and also it is an important key regulator for the immune cells.

It was found that the shift from oxidative phosphorylation to aerobic glycolysis has been associated with mutation or loss of function of the tumor-suppressor genes with the activation protumoral pathways, such as: Nuclear factor kappa-light-chain-enhancer of activated B-cells, protein kinase B (Akt), epidermal growth factor, insulin-like growth factor I, phosphoinositol 3-kinase, mammalian target of rapamycin, Kirsten rat sarcoma viral oncogene homolog, AMP-activated protein kinase, and HIF-1α.[9]

Several metabolic pathways were incriminated in the progression of prostate cancer ranging from cholesterol biosynthesis to electron chain anomalies.[10] These electron chain anomalies are also associated with the upregulation of HIF-1α, a molecule also intrinsically linked to hypoxia, ergo to lactate.

It is widely accepted/known that HIF-1α upregulates the genes in the cancer cells and tumor-associated fibroblasts (TAFs) for: Glucose transporter 1, monocarboxylate transporter four (MCT-4) and lactate dehydrogenase A (LDH-A) on an oxygen-independent manner. These processes generate high concentrations of lactate in the stroma and a high precursor pool for the pentose-phosphate pathway (PPP) and elevated concentrations of nicotinamide adenine dinucleotide phosphate (NADPH).[11] The glutamine metabolism is also affected by the enhancement of the glutaminolysis and adenosine triphosphate (ATP) production.[12] Glutaminolysis is a process that is not hampered by ROS, and thus provides an alternative energy source to a cell with anomalous mitochondrial functions such as in the tumor cell.[13],[14] Another contributor in the secretion of lactate in this context is the tumor-specific isoform of pyruvate kinase (PK) M2, which converts phosphoenolpyruvate into pyruvate. By doing so, this enzyme shifts the carbohydrate catabolism from ATP production to furnishing magisterial precursors, such as lactate, giving a proliferative edge to tumor cells expressing this phenotype.[15]

All these metabolic changes are directed to an enhanced proliferative state of the cancer cells, by assuring a high pool of precursor molecules for nucleic acids and carbon skeletons for macromolecules, but at apparent cost of energetic inefficiency, amended by their symbiosis with TAMs, which will be discussed further in the current review.

Tumors are complex conglomerates of cells intertwined in a perpetual exchange of cytokines and metabolites. The prostate carcinoma is characterized by several cell types as follows: Tumor cells derived from rare luminal epithelial stem cells[16] or basal cells[17] of the prostate glandular epithelium, and stromal cells associated with the tumor. These stromal cells are consisted the following: Lymphocytes and macrophages, TAFs and myofibroblasts, endothelial cells and bone marrow–derived stem/progenitor cells.[18] Due to the prostate's histological structure, the epithelium proliferation is regulated by the underlying stroma. Thus, in the neoplastic transformation, the stromal cell population plays a double role. Initially, they impede tumor development by forming a physical and immunological barrier between the neoplastic and healthy tissue, but as the tumor develops and starts secreting chemokines, cytokines, and growth factors, the stromal cells are reprogrammed at an epigenetic level leading to the creation of a symbiosis between the stroma and the tumor.[19] Furthermore, the symbiosis will provide nutrients and ensure an immunosuppressed, metastatic-inducing environment. The neoplastic cells in turn activate the stroma and ensure that its proliferation is maintained by recruiting bone marrow–derived stem/progenitor cells.[20]

In this whole process, there are two key components which regulate it: Lactate and M2 macrophages.

First step: Immunosuppression of the T lymphocytes

Tumor-produced lactate has a multipronged attack on the immune system. Due to its acidic nature, the pH in the tumor stroma can reach values between 6.0 and 6.5. At these values, tumor infiltrating T-cells cytolytic response and cytokine secretion are diminished. Moreover, extracellular lactate, at levels recorded in the tumor stroma inhibited the differentiation of monocytes and dendritic cells, synergically with impairing dendritic and cytotoxic T-cells cytokine production. Activated T-cells use glycolysis as a mean to sustain energy demands, and this process is influenced by the ratio of lactate inside T-cells and outside them. The excess lactate present in the tumor microenvironment can offset this ratio, thus, rendering the glycolysis inefficient, consequently impairing cytotoxic function CD8+ T-cells.[21]

A key player in cancer immune evasion is the Treg-cell. Its immunosuppressive phenotype (CTLA-4+; TIM-3+, PD-1+) and abundance in situ pledge to their role as a capital factor in tumor immune evasion.[22] As a matter of fact, Treg-cells (CD8+ Foxp3+) have been correlated with immunosuppressive capabilities in prostate cancer.[23] Therefore, as mounting evidence show, if there are deregulations of the stromal pH through lactate excess, the proliferation and function of Treg-cells will not be affected detrimentally; their energy metabolism is characterized by fatty acid oxidation. Consequently, lactate acid can upregulate an immunotolerant environment.

Due to its specificity as an epithelial cancer, in the development of prostate carcinoma, tumor cells can undergo a transdifferentiation process, epithelial immune cell-like transition, in which cancer cells acquire traits specific to immune cells, such as immune suppressive cytokines production and immune suppressive clusters of differentiation (CD83, CD200). This tumor secreted cytokines enhance the recruitment of Treg-cells, further enhancing the lactate induced immune tolerance of the tumor and the presence of CD 200 on the prostate cancer cell will greatly diminish the cytotoxic NK cell-mediated response.[24]

As it will be discussed in the next topic of our review, lactate acts as an activator for HIF-1α which in turn will upregulate the production of arginase 1 (ARG 1) by the M2 macrophages, with deleterious effect on the immune surveillance of the tumor microenvironment. ARG 1 is creating a hostile environment for T2 helper cells by depleting the L-ARG from the tumor milieu, thus, inducing a weak cytotoxic response further down the immune response.[25],[26] Due to ARG1 is a key enzyme in the synthesis of polyamines; it is capital to cellular proliferation.[27] ARG1, glutamate pyruvate transaminase, and glutamine synthetase are all present in abundance in the lactate-stimulated TAMs proteome.[28] These high levels of ARG1 are thus a key component in a positive feedback loop promoting immune suppression at tumor site: ARG1 ensures a steady production of polyamines promoting tumor growth, the tumor creates lactate that will maintain the HIF-1α active in M2 macrophages, which in turn will secrete ARG1. Noteworthy is the fact that the upregulation of the secretion of ARG1, and the M2 polarization is also characteristic of the infestation with Schistosoma mansoni[29] providing a tight bond between infectious disease, inflammation, and cancer.

Tumor lactate overproduction and glutaminolysis are not the only metabolic pathways correlated with immune evasion. More and more evidence account for products of deregulated lipid and adenosine metabolism with T-cell suppression effects, such as indoleamine 2, 3-dioxygenase.[30],[31]

Lactate produced by the cancer cell and TAMs will consequently cripple any cytotoxic T-cell or NK cell-mediated tumor in situ response and will provide a proliferative advantage to Treg-cells promoting immunological tolerance at the tumor site.

Second step: M2 activation

Macrophages are active players in the processes of maintaining tissue homeostasis such as fighting infections, resolving acute inflammation, regulating the response of the tissues to exposure of microenvironmental signals.

Analogous to lymphocyte T helper classification, macrophages are generally classified into M1 and M2 phenotypes. Studies revealed that M2 phenotype is highly present in the tumor microenvironment, thus obtaining the name of TAM. It has been shown that the majority of M2 macrophages are highly distributed within the tumor comparing to the benign areas that surround the tumor.[28] Several studies have outlined that increased number of TAM and a particular membrane phenotype, overexpression of MCT-1 and MCT-4, at patients with prostate cancer is associated with a bad prognostic.[32]

Lactate produced through aerobic glycolysis can be a potent agent in triggering the remodeling of tumor stroma in order to facilitate metastasis. As a result of lactate build-up in the stroma, there will be a pH drop, down to 6–6.5, which in turn will induce the synthesis, by the prostate neoplastic cells, of matrix metalloproteinase 2 and 9 (MMP-2, MMP-9).[33],[34] MMPs are capital for metastasis because they degrade basement membranes and enhance tumor cell migration.[35] In addition, lactate triggers the development of a specific cancer cell and TAFs protein phenotype (MCT-1+, PKM2+, carbon anhydrase IX+ [CAIX+]).[36] Monocarboxylic acid transporters are symporters that export lactate, pyruvate, and butyrate through the plasma membrane of both tumor cells and TAFs. On the other hand, the tumor cell exports lactate to TAFs via MCT-4 and the TAFs retrieve it through MCT-1 as an energy substrate.[37] However, in some cases, especially in prostate cancer, the process can be reversed, and the TAFs will provide the lactate, and the tumor cells will utilize it, giving them a proliferative edge.[38] CAIX plays an important role in acidifying the stroma and promoting epithelial mesenchymal transdifferentiation of prostate carcinoma cells, a development pattern associated with rapid metastasis.

Furthermore, lactate will trigger the M2 polarization of the macrophages, attracted by the inflammation created by the malign proliferation in the tumor's stroma from a cytotoxic and inflammatory M1 phenotype to a more “tumor friendly” M2 phenotype.

By triggering these mechanisms, lactate promotes the metastatic dissemination of the prostate carcinoma and in the same time diminishing the reactivity of the immune system toward cancer cells.

Moreover, TAMs play an important role in the migration and tumor invasion processes by inducing an epithelial-mesenchymal transition program through the nuclear factor-κ-mediated Snai1 stabilization of cancer cells. One study provides information that M2 macrophages isolated from the prostate carcinoma have a specific secretion profile interleukin-10 (IL-10) high-IL-2 low. Apparently, IL-6, produced by the cancer cells and stromal-derived factor 1, produced by TAMs are mandatory for the M2 polarization.

Although there are solid correlation between malignancy and the M2 phenotype such as extracapsular expansion and biochemical relapse in prostate cancer, there is evidence that the seemingly protective M1 macrophagic phenotype, associated with organ-confined prostate carcinoma, is also associated with tumor dissemination.[39]

Lactate acts on the M2 macrophage by inducing the activation of HIF-1α which will entail the secretion of VEGF alpha (VEGFa) and ARG1 triggering the development of neovascularization of the tumor and immunosuppressive and remodeling process regarding the tumor extracellular matrix. VEGFa levels regulated by lactate via activation of HIF-1α were comparable with the ones exhibited by hypoxia conditions. ARG1 also plays an indirect role in angiogenesis through reorganization of the tumor extracellular matrix, converting L-ornithine in L-proline and regulating collagen synthesis[26] and in extenso blood vessel formation. The IL-4 and IL-13, two of the best known inducers of the M2 macrophage phenotype[40] can stimulate the production of ARG1 but the activation HIF-1α is mandatory for the expression of the secretion of both ARG1 and VEGFa. Even though M2 polarization remains an incompletely described phenomenon, the metabolic approach to this topic is yielding more and more relevant insights into this matter. The PPP is an important pathway in synthesizing pentose and NADPH, and it is upregulated in activated macrophages.[41] Carbohydrate kinase-like protein, a PPP regulating protein has been shown to be under expressed in M1 macrophages but increased signal transducer and activator of transcription 3 phosphorylation, and sensitized macrophages stimulated via IL-4 to M2 polarization.[42]

In the tumor microenvironment, lactate can trigger an autocrine response in the endothelial cells increasing the production of IL-8/CXCL8 and activating angiogenesis.[12] Moreover, lactate can be harvested from the tumor microenvironment through MCT-1, and it activates HIF-1α which will enlist the upregulation of basic fibroblast growth factor accelerating the angiogenic process.[39]

As mounting evidence shows, lactate is an emerging factor in the M2 polarization of macrophages. As a working hypothesis, lactate excess in tumor stroma, by polarizing macrophages to a M2 phenotype generates an immunotolerant environment, activates and enhance angiogenesis and promotes a positive feedback loop between TAFs, M2 macrophages, and tumor cells with the ultimate goal to promote tumor growth and metastasis.

 > Clinical Outlines Top

Reactive oxygen species (ROS) are required for the processes of DNA and RNA alterations that lead to genomic instability, culminating with tumoral cells damage. Lactate, with its antioxidant properties, can lead to a diminished quantity of ROS induced by radiotherapy in the tumor milieu, thus, blunting the patient response to radiotherapy in individuals with a tumor phenotype proficient in producing large quantities of lactic acid.[43]

As stated previously, lactate is produced by the tumoral cells and several other cells from the tumoral microenvironment, as a consequence of hypoxia, favoring tumoral invasion, metastasis and angiogenesis. Furthermore, to the vicious circle of the tumoral progression adds the acidification of the tumoral stroma, which induces an immunosuppression state. Recently, scientists thought that inhibiting LDH-A, which normally converts the transformation of pyruvate to lactate, leads to inhibition of tumoral proliferation.[44] Thereby, the inhibitors of glycolysis could be used as a new generation of therapeutics in castrate resistant prostate cancer.[45]

Immunotherapy evolved recently as a promising alternative in combating cancer. Sipuleucel-T has shown an improved benefit in OS.[46] It is a vaccine consisted of antigen-presenting cells that has been activated with a prostate antigen, leading to the initiation of an immune response. Due to the fact that, lactate is an inhibitor of the T effector cells, may lead to treatment failure. Thus, serum lactate and LDH should be monitored at patients receiving immunotherapy. It is possible that in the near future clinicians may add specific inhibitors of lactate or LDH in combination with immunotherapy.

Another strategy of exploring the impact of lactate in prostate cancer is the study of MCT.[47] MCT-1 is known be an important regulator of lactate HIF activation, related to tumoral progression and angiogenesis. Indeed, a pathology analysis from 480 patients with a median age of 64 years following radical prostatectomy with no previous hormonal therapy revealed increased MCT-4 expression in cancer-associated fibroblasts with concomitant high MCT-1 expression, which is associated with poor prognosis. Blocking the MCT's may play a potential role in the oncological field, targeting aggressive tumor development. Metformin, which is a respiratory complex 1 disruptor, seems to induce MCT inhibition and is associated with an improved prognostic in prostate cancer.[48]

In addition, TAM is important monitoring parameters of the progression of the disease.[49] It was found that increased TAM density is correlated with a raised Gleason score and clinical stage. Furthermore, they are associated with polysialic acid alteration and progression of the disease. One receptor of tyrosine kinases, Tie-2, is a stemness marker and is expressed by tumoral monocytes form the prostate tumoral mileu, which compared to TAM's, have a stronger pro-angiogenic capacity and are correlated with chemoresistance.[50]

Depending on the stage of the disease, lactate, the old molecule, now with a double edge sword role, may play an important role in monitoring the clinical outcome, not only in patients with prostate cancer, but also at those suffering from other forms.

 > Conclusion Top

Targeting lactic acid altered metabolism in prostate cancer may play in the future an important role. Inhibiting lactate will not only stop the progression of cancer through cellular deprivation, and blocking tumoral associated stromal cells and their negative consequences, but will also counteract its immunosuppressive mechanisms. Thus, this oncological strategy will be effective in combination therapy, with chemo- and immune-therapy and also, it will be useful in combating tumoral resistance.


The authors are grateful to “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania, Department of Medical Oncology and Radiotherapy for supporting their work.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

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