Metabolic remodeling is a step that is absolutely required for the malignant transformation of cells. Being able to rapidly and continuously divide is the key feature of cancer cells. In order to maintain this proliferative profile, cancer cells must be able to rapidly generate ATP, maintain an appropriate reduction-oxidation (redox) balance and produce enough biomass. To meet these requirements, cancer cells need to undergo extensive metabolic reprogramming. Medicines that target cancer metabolism, for example antimetabolites that inhibit nucleotide and DNA biosynthesis, have shown success in treating various types of cancers. Yet, targeting a single enzyme or pathway is often not sufficient as resistance and relapse often follow. In addition, toxicity is also a common problem as these drugs unequivocally inhibit many other proliferating non-malignant cells such as bone marrow. Recently, with the exciting advances in immunotherapy, new research has been looking into the possibility of targeting metabolic pathways in tumor microenvironment (TME) and cancer cells to enhance the efficacy of some immunotherapies. Here, in this article, we would like to explore the potential as well as address the problems of combining cancer metabolic therapy with immunotherapy. Now, before diving into specific therapies and targets, we will take a brief refresher of the biochemistry and cellular metabolism of cells.
Part I – Metabolism at a glimpse: a brief overview of major metabolic pathways and their roles in shaping immune responses.
There are six major metabolic pathways taking place in a cell: 1) the glycolytic pathway (glycolysis), 2) tricarboxylic acid (TCA) cycle, 3) fatty acid oxidation, 4) pentose phosphate pathway (PPP), 5) fatty acid synthesis and 6) amino acid metabolism. Despite each pathway utilizing distinct substrates and taking place in various cellular compartments, they are all closely interconnected, as the products or intermediates of one often end up as substrates fuelling others. Together, all six pathways promote cell homeostasis, survival, growth and proliferation.
Part II – Metabolic changes associated with T cell activation.
Upon activation, T cells undergo dramatic metabolic remodelling. Failing to accomplish metabolic reprogramming, and nutrient deprivation, such as a lack of glucose and glutamine, leads to impaired T cell function. In their quiescent state, naïve and memory T cells primarily rely on OXPHOS, a relatively slow yet highly efficient way to generate ATP. Upon activation, naïve T cells quickly shift from OXPHOS to aerobic glycolysis, a phenomenon known as the Warburg effect. To help with the metabolic change, other transcriptional and translational modifications also occur, such as increased generation of glucose transporter Glut1 to facilitate the rapid uptake of glucose. In cells undergoing the Warburg effect, instead of being converted to acetyl-CoA, pyruvate undergoes fermentation and is converted to lactate. As mentioned above, glycolysis followed by pyruvate fermentation only produces 2 ATP per glucose. Why would effector T cells choose such an inefficient way to generate energy? One interpretation is that aerobic glycolysis is a relatively faster way to generate ATP, which is not limited by the number of cellular mitochondria. In addition, it also generates massive amounts of metabolic intermediates that feed into other crucial biosynthetic pathways such as the PPP for nucleotide and amino acid synthesis and fatty acid synthesis. In summary, aerobic glycolysis provides active T cells with a more readily available supply of energy and substrates for the biosynthesis of essential molecules for cell division.
Yet, recent research suggests that the Warburg effect may have additional purposes other than just ATP generation. For example, the Pearce group from the Washington School of Medicine demonstrated that the metabolic shift to aerobic glycolysis in active T cells is not necessary for ATP generation, but plays an important role in aiding the production of IFN-γ. They showed that in a quiescent state when the cells mainly utilize OXPHOS, a key glycolytic enzyme GAPDH post-transcriptionally regulates T cell function by binding the cytosolic mRNA of IFN-γ and thereby inhibit glycolytic cycle, allowing for the release of IFN-γ mRNA, thus initiating the translation and production of the cytokine. In summary, naïve and memory T cells rely predominantly on OXPHOS and fatty acid oxidation for basal ATP production, whereas activated T cells undergo a metabolic reprogramming and rely heavily on aerobic glycolysis for energy production and effector T cell function.
Metabolic profile also has an important effect on T cell differentiation. The Rathmell group from Duke University showed that effector T helper cells (Th1, Th2 and Th17) preferentially rely on aerobic glycolysis over mitochondrial metabolism, whereas induced Tregs show a minimal increase in Glut1 expression and primarily engage in lipid oxidation and OXPHOS. Interestingly, not only did they observe that different Th subsets have specific metabolic preferences, they also showed that manipulating metabolism in vitro by changing nutrient availability could skew CD4+ T cell differentiation. Adding fatty acids to a T cell culture or inhibiting the mTOR pathway favored Treg differentiation. Similarly, the Chi group from St. Jude’s Children’s Hospital in Tennessee showed that HIF-1α, whose activity is regulated by mTOR, promotes glycolysis and Th17 differentiation. Defects in HIF-1α result in impaired Th17 differentiation and increased Treg formation. Despite the growing interest in immune cell metabolism and its therapeutic potential, further studies are needed to investigate the correlation between extracellular nutrient availability with T cell activation and differentiation in different disease settings.
Part III – Metabolism and cancer immunotherapy.
Tumour cells can utilize specific metabolic approaches, like limiting glucose availability, to dampen the immune response and enhance T cell exhaustion. Like any rapidly proliferating cell, malignant cancer cells also undergo extensive metabolic changes, shifting from OXPHOS to aerobic glycolysis (Warburg effect). Therefore, key metabolic pathways and substrates of tumour cells often greatly overlap with the ones utilized by activated T cells. Yet, due to genomic instability and a high mutation rate, cancer cells also exhibit high levels of metabolic variability, flexibility and efficiency, allowing them to adapt to the super heterogeneous and limited nutrient and oxygen levels within the tumour microenvironment much better than T cells. These metabolic advantages of tumor cells contribute to the severe glucose deprivation and lactate accumulation within the tumour microenvironment, thus asserting great metabolic pressures for effector T cells. Another factor that contributes to glucose scarcity is the unique structure of solid tumours. Due to the excessive production of growth factors, the blood and lymphatic networks within solid tumours are often functionally impaired and leaky, which severely limits their ability to maintain normal nutrient and gas exchange within the tumour. Altogether, the tremendous metabolic pressure is a huge challenge for effector T cells to maintain proper function in the tumor microenvironment.
Recent studies observe that Tregs have a metabolic advantage over effector T cells in the tumor microenvironment, which contributes to their survival and accumulation with tumor progression. In contrast to effector T cells, whose functions are severely impaired by the limitation of nutritients like glucose and glutamine in the TME, Tregs cope with the environment much better through various metabolic adjustments. The Peng group from the St. Louis University School of Medicine showed that elevated glucose consumption by Tregs induced cell cycle arrest and senescence in effector T cells. In addition, other studies have shown that Tregs in the tumor microenvironment can also suppress effector T cell responses by degrading extracellular ATP to adenosine via the enzymes CD39 and CD73.
Can we target cellular metabolism to either inhibit cancer cell proliferation or reinvigorate the antitumor immune response? Targeting specific metabolic pathways and metabolites may be an effective way to inhibit tumor growth and enhance immunotherapies. For instance, altered fatty acid metabolism has been reported to support cancer growth and enhance cancer malignancy. Targeting the fatty acid metabolism pathway might be a therapeutic direction that not only inhibits tumor growth, but may also prevent Treg differentiation and accumulation in these tumors. Recently, there has been a growing interest in the metabolic target mTOR. Targeting mTOR can induce metabolic stress and promote apoptosis of cancer cells.
Despite the great potential of targeting the metabolism of cancer cells in combination with current cancer immunotherapies, several caveats exist. First, activated T cells and cancer cells often utilize similar metabolic pathways and cancer cells are often more efficient in taking advantage of these pathways. Therefore, enhancing the cellular metabolism of immune cells may at the same time improve cancer cell survival. Secondly, cancers are extremely heterogeneous and plastic systems. Even within the same solid tumor, cells at different locations (invasive margins versus tumor cores) may have distinct metabolic profiles. Targeting a single metabolic pathway may not be sufficient to eliminate all malignant cells at once, and eliminating only subsets of cancer cells has the risk of expanding the rest of the cancer cells. More importantly, genome instability gives cancer cells the ability to switch between metabolic pathways, and thus may turn them resistant to a single type of treatment. Moreover, different types of cancer have distinct metabolic preferences – aerobic glycolysis is less important for slow growing tumors compared to fast growing ones. Therefore, how to address this intratumoral and intertumoral heterogeneity remains a big challenge in cancer immune-metabolic therapies.
In summary, targeting the metabolic pathways of cancer cells and immune cells has huge therapeutic potential, but more studies are required to (1) characterize the extremely heterogenous tumor microenvironment in depth across different cancer types, (2) better understand how the tumor microenvironment shapes the metabolism of key tumor-infiltrating immune cells.
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