Through the successes of checkpoint blockade and adoptive cellular therapy, immunotherapy has become an established treatment modality for cancer. Cellular metabolism has emerged as a critical determinant of the viability and function of both cancer cells and immune cells. In order to sustain prodigious anabolic needs, tumours employ a specialized metabolism that differs from untransformed somatic cells. This metabolism leads to a tumour microenvironment that is commonly acidic, hypoxic and/or depleted of critical nutrients required by immune cells. In this context, tumour metabolism itself is a checkpoint that can limit immune-mediated tumour destruction. Because our understanding of immune cell metabolism and cancer metabolism has grown significantly in the past decade, we are on the cusp of being able to unravel the interaction of cancer cell metabolism and immune metabolism in therapeutically meaningful ways. Although there are metabolic processes that are seemingly fundamental to both cancer and responding immune cells, metabolic heterogeneity and plasticity may serve to distinguish the two. As such, understanding the differential metabolic requirements of the diverse cells that comprise an immune response to cancer offers an opportunity to selectively regulate immune cell function. Such a nuanced evaluation of cancer and immune metabolism can uncover metabolic vulnerabilities and therapeutic windows upon which to intervene for enhanced immunotherapy.
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J.D.P. is a scientific founder, a paid consultant and has equity in Dracen Pharmaceuticals. Technology arising in part from the studies described herein was patented by Johns Hopkins University and subsequently licensed to Dracen Pharmaceuticals (JHU083 is currently labelled as DRP-083). R.D.L. and J.D.P. are inventors for pending patent application no. PCT/US16/44829 submitted by Johns Hopkins University that covers the use of glutamine analogues, such as JHU083 (DRP-083), for cancer immunotherapy. J.D.P has been a paid consultant for Corvus Pharmaceuticals and has equity in the company.
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- Oxidative phosphorylation
(OXPHOS). A highly efficient form of cellular respiration synthesizing ATP from the phosphorylation of ADP using electrochemical potential energy generated by the transfer of electrons from NADH or FADH2 to oxygen through a series of mitochondrial electron carriers.
- Immune checkpoint pathways
Pathways mediated by cell surface proteins on immune cells, such as PD1 or CTLA4, that serve to suppress the immune response, which can be activated by ligands within the tumour microenvironment or draining lymph nodes.
- Chimeric antigen receptor T cells
(CAR T cells). T cells harvested from a patient’s blood and genetically modified to express a special receptor that can recognize and respond to specific, predefined molecular targets on tumour cells.
- Hexosamine biosynthesis pathway
(HBP). A branch of glycolysis that generates building blocks used for glycosylation of proteins and lipids.
- Pentose phosphate pathway
(PPP). A metabolic branch of glycolysis generating NADPH, used for fatty acid synthesis and redox homeostasis, and 5-carbon sugars used in nucleotide synthesis.
- Nuclear factor of activated T cells
(NFAT). A calcium-dependent transcription factor activated in response to T cell receptor stimulation. Cooperation with the AP-1 transcription factor results in a productive immune response and transcription of pro-inflammatory cytokines, such as IL-2 and interferon-γ.
The loss of metabolic intermediates in a metabolic pathway (particularly the tricarboxylic acid cycle) owing to consumption or degradation.
The process of replenishing intermediates of the tricarboxylic acid cycle to support biosynthesis.
- De novo lipid synthesis
The cellular biosynthesis of fatty acids, triglycerides, cholesterol and other lipids from carbohydrates or other non-lipid precursors.
- 2-Oxoglutarate-dependent dioxygenases
(2OGDD). A family of enzymes that catalyse the hydroxylation of macromolecules, often as a prerequisite to demethylation, reliant on α-ketoglutarate, Fe2+, ascorbate and oxygen as cofactors.
- Major histocompatibility complex
(MHC). MHC class I (MHC-I) is expressed on all nucleated cells, a molecular complex presenting intracellular peptide epitopes for CD8+ T cell receptor recognition. Also expressed on antigen-presenting cells, allowing initial antigen-specific activation of cytotoxic CD8+ T cells. MHC-II is highly expressed on antigen-presenting cells for presenting antigenic epitopes for CD4+ T cell receptor recognition and activation.
- Antigen cross-presentation
The ability of antigen-presenting cells to process extracellular antigens and present them to CD8+ T cells through major histocompatibility complex class 1 presentation.
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Leone, R.D., Powell, J.D. Metabolism of immune cells in cancer. Nat Rev Cancer 20, 516–531 (2020). https://doi.org/10.1038/s41568-020-0273-y
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