Immunotherapy has become a pillar of cancer treatment and has demonstrated great success in many tumour types including non-small cell lung cancer, melanoma and breast cancer. In particular the “Immune checkpoint inhibitors” have improved outcomes for some of the most dismal cancers. As such, the discovery of the two inhibitory receptors that are primarily targeted (PD-1 and CTLA-4) was awarded the Nobel prize in physiology and medicine in 2018 (Nobel Prize, 2018). While responders to the checkpoint inhibitors often experience complete responses and extended overall survival only 40% at most respond, the remaining 60% non-responders have no benefit (Marin-Acevedo et al., 2018). Therefore resistance to this form of immunotherapy is a significant unmet clinical challenge.
T-Cell metabolic pathways & Inflammation
Tumour infiltrating lymphocytes (TIL’s), the target of the checkpoint inhibitors, exist in a state of dysfunction and exhaustion, characterised by reductions in cytokines and gene expression of key cytotoxic molecules such as IFN-gamma, GzmA, GzmB and TNF-alpha, which prevents the generation of an appropriate anti-cancer response (Domblides et al., 2019, Jiang et al., 2015). Immunosuppressive signalling within the tumour microenvironment (TME) maintains this state of T-cell dysfunction via a number of mechanisms (Ohta et al., 2012, Schlosser et al., 2014, Wahl et al., 2006). The emerging field of immunometabolism studies how metabolic pathways guides immunity and how metabolites from these pathways act as signalling molecules instructing the modality of an immune response (O'Neill et al., 2016). In T-cells the cellular choice of metabolic pathways can drive the expression of key effector cytokines and result in optimal conditions for anti-tumour immunity, or they can instruct the conditions necessary for wound healing or anti-inflammatory immunity (Buck et al., 2017).
T-Cell metabolism drives immunity
A defining hallmark of cancer is dysregulated cellular metabolism, often resulting in the preferred use of alternative metabolic pathways (Hanahan and Weinberg, 2011, Koppenol et al., 2011). The preference for glucose for example, particularly in dividing tumour cells, drives a reduction in the concentration of glucose within the TME (Chang et al., 2015b). Immune cells, including TIL’s rely on glucose as a fuel for anti-tumour immunity in both the production of effector cytokines as well as cytotoxic responses (Cham et al., 2008, Jacobs et al., 2008, Frauwirth et al., 2002). Another consequence of high glycolytic activity within tumour is the release of lactate into the TME, lactate exists in solution as lactic acid and the consequential acidification of the TME contributes to defective signalling of the T-cell receptor (TCR) as well as dysfunctional anti-tumour immune responses (Chalmin et al., 2018).
Lactate metabolism promotes FoxP3 expression in T-Cells
Lactate is also taken up by TIL’s and affects their polarisation via the reduction of T-bet and promotion of FoxP3 expression (Comito et al., 2019). Other nutrients are altered within the TME as well, the amino acid glutamine can be used a fuel for tumour cells to produce proteins necessary for growth and tumour often express higher levels of the glutamine transporter on their cell surfaces, hence glutamine can be similarly taken up by cancer cells preferentially (Chang et al., 2015a). Glutamine is a vital amino acid for TIL’s as glutamine metabolism is involved in the generation of an effector response, critically TREG’s do not rely glutamine metabolism whereas conventional anti-tumour effector subsets do, whereby in the absence of glutamine T-cells with high FoxP3 expression and suppressive functions are induced (Carr et al., 2010, Johnson et al., 2018, Metzler et al., 2016). Therefore at a basic level there is competition between tumour cells and infiltrating immune cells, indeed studies have shown that in the TME, TIL’s uptake less glucose than cancer cells (Chang et al., 2015a).
TIL's and AMPK signalling
TIL’s often resort to any available means of generating energy due to this challenging metabolic environment. The energy sensor AMPK acts to restrict the activity of mTORC1, a vital signalling molecule within T-cells and involved in the generation of a pro-inflammatory/anti-tumour effector profile (O'Neill and Hardie, 2013, Rolf et al., 2013, Salt et al., 1998). When T-cells enter into a situation of nutrient deprivation AMPK becomes active, driving a catabolic metabolic phenotype, often oxidative phosphorylation and fatty acid oxidation are the main pathways promoted by AMPK, and these pathways are associated with quiescent metabolism and Treg’s. mTORC1, on the other hand, drives a more anabolic phenotype with the synthesis of new fatty acids important for growth and proliferation as well as glycolysis to allow for bioactive intermediates to be shuttled into other pathways to be used for other important activities such as protein synthesis, ribo-nucleotide synthesis and redox balance (Düvel et al., 2010, O'Neill et al., 2016).
Figure 1: An overview of mTOR mediated immunity in T-cells
T-Cell metabolism in the tumour microenvironment
We know that many of the immune checkpoint receptors act in part through modulating metabolic pathways within T-cells. Inhibitory checkpoint receptors such as PD-1, CTLA-4 and LAG3 reduce the glycolytic capacity of T-cells promoting a suppressive phenotype, whereas the stimulatory checkpoint receptors GITR and 4-1BB promote metabolic pathways associated with anti-tumour effector profiles by blocking fatty acid oxidation and promoting glycolysis (Patsoukis et al., 2015, Parry et al., 2005, Previte et al., 2019, He et al., 2017, Sabharwal et al., 2018). Indeed other signals within the TME effect the metabolic pathways used by TIL’s, TGF-beta for example is a immunosuppressive cytokine often overexpressed in tumours and is associated with the exclusion of immune cells from the TME (Li et al., 2006, Mariathasan et al., 2018).TGF-beta is now recognised to effect mTORC1 signalling in some immune cell subsets (Kanamori et al., 2018, Komai et al., 2018).
Figure 2: Signals from the microenvironment impact on metabolic pathways and anti-tumour immunity
T-Cell metabolism inhibitors
Understanding how each effector subtype of T-cell uses metabolic pathways to develop its response is vital to understanding the dysfunction within the tumour. Indeed it is also possible that in targeting metabolic pathways we can bring about better responses in patients treated with immunotherapy. There are currently a number of early stage clinical trials examining the effect of targeting metabolism for combination with immunotherapy Glutamine metabolism is being targeted with CB-839 (a GLS inhibitor) in combination with Nivolumab in advanced renal cell carcinoma, melanoma and NSCLC (NCT02771626). Metformin is also currently under investigation in combination with both Pembrolizumab and Nivolumab for use in NSCLC and melanoma (NCT03048500, NCT03311308). Targeting glucose metabolism with metformin may prove to have both favourable and unfavourable consequences, by reducing glucose consumption in cancer cells it may free up glucose for use by TIL’s, however as a potent activator of AMPK, metformin may inadvertently promote a suppressive metabolic profile in immune cells.
In summary the emerging field of immunometabolism hopes to shed light on how metabolism fuels robust anti-tumour immune responses. In cancer the combination of targeting metabolism and immunotherapy may yield better response rates by promoting anti-tumour responses from reinvigorated TIL’s.
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