Introduction

Cancers are polygenic diseases initiated by multiple oncogenic factors that dysregulate the expression of tumor suppressor genes and/or proto-oncogenes leading to malignant progression [1]. The neoplastic tissue is comprised of heterogeneous population of tumor cells, in a milieu of immune (e.g., myeloid cells, lymphocytes, and natural-killer cells), and non-immune cells (e.g., fibroblasts and endothelial cells) embedded in the extracellular matrix with a plethora of cytokines and chemokines, known as tumor microenvironment (TME) [2,3,4]. TME has dynamic attributes with pro- and anti-tumorigenic properties, which can also influence drug responses [5]. Tumor cells evade host-immunosurveillance by recruiting surplus of immunosuppressive cells including T regulatory cells (Tregs) [6, 7] and myeloid-derived suppressive cells (MDSCs) [6], which suppress the proliferation of cytotoxic T cells (CTLs) and favor malignant progression [8]. Amongst these suppressive cells, Tregs are considered as the master-regulatory cells, which not only secrete cytokines that promote onset and proliferation of malignancies, but also play indispensable roles in the induction of neo-angiogenesis and metastasis [9,10,11,12]. Accumulating evidence suggest that Treg infiltration was evident in vast majority of solid tumors including breast [7], colon [6], pancreatic [13] and ovarian cancer [9]. Tumors samples from advanced stages of cancer exhibit higher infiltration of Tregs, compared with samples obtained from early stages of cancer [14]. Moreover, meta-data analyses showed that higher Treg infiltration is negatively correlated with cytotoxic CD8+ T cell infiltration and that is associated with poor-disease prognosis [15]. Currently, it is believed that Treg infiltration favors tumor progression and dampens anti-tumor immune responses; thus, it is essential to understand the progression and functions of Tregs in the TME [16, 17].

Tumor cells adapt to multiple metabolic processes including glycolysis, oxidative phosphorylation (OXPHOS) and fatty acid metabolism to obtain energy for their survival and progression in adverse tumor milieu [18]. Moreover, the differentiation of T cells within the TME is indirectly regulated by tumor-mediated metabolites and favors tumor progression [19]. Within the TME, metabolic reprogramming of T cells is initiated by the activation of T cell receptor (TCR) signaling along with various costimulatory molecules, resulting in the production of sufficient ATP to meet energy requirements for T cell proliferation and effector functions [20]. Interestingly, T cells isolated from the TME frequently exhibit exhaustive T cell markers and possess distinct metabolic signatures including reduction in the uptake of glucose and upregulation of reactive oxygen species (ROS) [21]. These metabolic defects could be circumvented and partially restored the activation of tumor-infiltrating CD8+ T cells (TILs) through the adequate supplementation of pyruvate and neutralization of ROS [21]. These reports suggest that tumor metabolic environment could alter the regulation, function and tumor-antigen recognition of T cells, leading to inadequate anti-tumor responses.

It has been reported that accumulation of lactate and carbon dioxide could efficiently reprogram the metabolic potentials of tumor cells, including elevated nutrient uptake and glucose metabolism and favor the differentiation of Tregs by inhibiting the infiltration of effector T cells within the TME [22, 23]. Moreover, hypoxic conditions as a result of increased tumor growth and oxygen deprivation stabilize the expression of hypoxia‐inducible factor 1‐α (HIF1‐α), which in turn mediates the induction of FoxP3 expression and favors Treg stability [24, 25]. Therefore, comprehensive analyses of malignancy-induced metabolic/hypoxic regulation of T cells can improve current immunotherapeutic modalities. Numerous studies have focused on the metabolic reprogramming of tumor cells and their influence over T cell function within the TME; however, limited data are available on the metabolic-induced alterations in Tregs in the TME. This review highlights the metabolic reprogramming of physicochemical characteristics of Tregs, their function, differentiation and crosstalk within the TME. Additionally, we focus on the potential metabolic pathways of Tregs within the TME, which may be targeted for improvement of prognosis and development of novel therapeutic strategies.

Metabolism in the tumor microenvironment

Tumor cells are characterized by their competence to adapt with altering environmental cues by exploiting various nutrients to uphold their necessitating anabolic requirements [3]. This sustained energy demand is accomplished by adequate supply of nutrients and oxygen via tumor vasculature [26]. Consequently, these extracellular nutrients are indispensable for cancer cells to meet their high-energy demand during rapid, uncontrolled proliferation [26]. Unlike normal cells, malignant cells have higher metabolic plasticity, which could reshape the environment even in nutrient-deprived conditions per se [27]. This plasticity has profound influence on tumor differentiation and gene expression within the TME [27]. In this context, Pavlova and colleagues classified tumor-associated metabolic modifications into six groups: (1) deregulation in glucose and amino acid metabolism, (2) altered nutrient uptake, (3) utilization of intermediates from citric acid cycle (TCA cycle)/glycolysis for the biosynthesis of nicotinamide adenine dinucleotide phosphate (NADPH), (4) increased nitrogen requirement, (5) variations in the regulation of metabolite-dependent gene expression and (6) interactions between metabolic pathways within the TME [27].

It has been reported that the highly proliferating cancer cells modify the metabolic components of the TME. For instance, malignant cells take up higher amount of glucose leading to the biosynthesis of large amount of lactate, which could influence many cell populations within the TME [28]. Higher accumulation of lactate creates an immune-subversive milieu by reducing dendritic and T cell activation and migration of tumor-associated macrophages/monocytes [28, 29]. Moreover, the excess accumulation of lactate polarizes resident macrophages to highly activated/ immunosuppressive M2 state and promotes angiogenesis [30, 31]. Excess levels of lactate also favor the biosynthesis of hyaluronic acid by fibroblasts, contributing to higher tumor invasiveness [32].

Hypoxia-inducible factor 1-alpha (HIF-1α) is the key transcriptional factor of hypoxic cells, a hallmark of the TME, and is a downstream target of glucose transporter-1 (GLUT-1) [33]. During hypoxic conditions, the higher glucose uptake by cancer cells could upregulate the stability of HIF-1α, which in turn leads to the attenuation of anti-tumor immune responses [34]. In HIF-1α-knocked-out murine models, the anti-tumor immune responses of CD8+ TILs improve through the activation of peroxisome-activated receptor α (PPARα) signaling and also elevated metabolism of fatty acids [

Change history

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Authors and Affiliations

  1. Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar

    Varun Sasidharan Nair, Reem Saleh & Salman M. Toor

  2. Department of Basic Medical Sciences, College of Medicine, Member of QU Health, Qatar University, Doha, Qatar

    Farhan S. Cyprian

  3. Biomedical Research Center, School of Science, Engineering and Environment, University of Salford, Manchester, M5 4WT, UK

    Eyad Elkord

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VN, RS and ST wrote the article and prepared figures/table. FC assisted in writing-review and editing. EE conceived the concept, acquired funds, supervised and performed writing-review and editing.

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Sasidharan Nair, V., Saleh, R., Toor, S.M. et al. Metabolic reprogramming of T regulatory cells in the hypoxic tumor microenvironment. Cancer Immunol Immunother 70, 2103–2121 (2021). https://doi.org/10.1007/s00262-020-02842-y

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