The microenvironment in cancerous tissues is immunosuppressive and pro-tumorigenic, whereas the microenvironment of tissues affected by chronic inflammatory disease is pro-inflammatory and ...anti-resolution. Despite these opposing immunological states, the metabolic states in the tissue microenvironments of cancer and inflammatory diseases are similar: both are hypoxic, show elevated levels of lactate and other metabolic by-products and have low levels of nutrients. In this Review, we describe how the bioavailability of lactate differs in the microenvironments of tumours and inflammatory diseases compared with normal tissues, thus contributing to the establishment of specific immunological states in disease. A clear understanding of the metabolic signature of tumours and inflammatory diseases will enable therapeutic intervention aimed at resetting the bioavailability of metabolites and correcting the dysregulated immunological state, triggering beneficial cytotoxic, inflammatory responses in tumours and immunosuppressive responses in chronic inflammation.
The development of immunotherapies over the past decade has resulted in a paradigm shift in the treatment of cancer. However, the majority of patients do not benefit from immunotherapy, presumably ...owing to insufficient reprogramming of the immunosuppressive tumour microenvironment (TME) and thus limited reinvigoration of antitumour immunity. Various metabolic machineries and nutrient-sensing mechanisms orchestrate the behaviour of immune cells in response to nutrient availability in the TME. Notably, tumour-infiltrating immune cells typically experience metabolic stress as a result of the dysregulated metabolic activity of tumour cells, leading to impaired antitumour immune responses. Moreover, the immune checkpoints that are often exploited by tumour cells to evade immunosurveillance have emerging roles in modulating the metabolic and functional activity of T cells. Thus, repurposing of drugs targeting cancer metabolism might synergistically enhance immunotherapy via metabolic reprogramming of the TME. In addition, interventions targeting the metabolic circuits that impede antitumour immunity have been developed, with several clinical trials underway. Herein, we discuss how these metabolic circuits regulate antitumour immunity and the possible approaches to targeting these pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments that could be used to better unleash the potential of adoptive cell therapies by enhancing T cell metabolism.
Cytotoxic CD8+ T cells are a key element of the adaptative immune system to protect the organism against infections and malignant cells. During their activation and response, T cells undergo ...different metabolic pathways to support their energetic needs according to their localization and function. However, it has also been recently appreciated that this metabolic reprogramming also directly supports T‐cell lineage differentiation. Accordingly, metabolic deficiencies and prolonged stress exposure can impact T‐cell differentiation and skew them into an exhausted state. Here, we review how metabolism defines CD8+ T‐cell differentiation and function. Moreover, we cover the principal metabolic dysregulation that promotes the exhausted phenotype under tumor or chronic virus conditions. Finally, we summarize recent strategies to reprogram impaired metabolic pathways to promote CD8+ T‐cell effector function and survival.
Recent progress in cancer immunotherapy emphasizes the importance of understanding immune-regulatory pathways in tumours. Dysfunction of antitumour T cells may be due to mechanisms that are ...evolutionarily conserved or acquired by somatic mutations. The dysfunctional state of T cells has been termed 'exhaustion', on the basis of similarities to dysfunctional T cells in chronic infections. However, despite shared properties, recent studies have identified marked differences between T cell dysfunction in cancer and chronic infection. In this Review, we discuss T cell-intrinsic molecular alterations and metabolic communication in the tumour microenvironment. Identification of the underlying molecular drivers of T cell dysfunction is essential for the continued progress of cancer research and therapy.
The endoplasmic reticulum (ER) is a critical organelle, storing the majority of calcium and governing protein translation. Thus, it is crucial to keep the homeostasis in all ER components and ...machineries. The ER stress sensor pathways, including IRE1/sXBP1, PERK/EIf2 and ATF6, orchestrate the major regulatory circuits to ensure ER homeostasis. The embryonic or postnatal lethality that occurs upon genetic depletion of these sensors reveals the essential role of the ER stress pathway in cell biology. In contrast, the impairment or excessive activation of ER stress has been reported to cause or aggravate several diseases such as atherosclerosis, diabetes, NAFDL/NASH, obesity and cancer. Being part of innate immunity, myeloid cells are the first immune cells entering the inflammation site. Upon entry into a metabolically stressed disease environment, activation of ER stress occurs within the myeloid compartment, leading to the modulation of their phenotype and functions. In this review, we discuss causes and consequences of ER stress activation in the myeloid compartment with a special focus on the crosstalk between ER, innate signaling and metabolic environments.
Evidence from mouse chronic viral infection models suggests that CD8
T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential ...for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8
T lymphocyte populations with high (PD-1
), intermediate (PD-1
) and no PD-1 expression (PD-1
) from non-small-cell lung cancer patients. PD-1
T cells showed a markedly different transcriptional and metabolic profile from PD-1
and PD-1
lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1
lymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1
cells was strongly predictive for both response and survival in a small cohort of non-small-cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention.
A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) ...respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36−/− T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.
Display omitted
•The tumor microenvironment is enriched with lipids and oxidized lipids•Dysfunctional CD8+ TILs increase CD36 expression and OxLDL uptake•OxLDL uptake via CD36 inhibits T cell effector functions through lipid peroxidation•GPX4 overexpression promotes CD8+ TIL functionality
Lipid accumulation is a common metabolic alteration in the tumor microenvironment. Xu et al. show that intratumoral CD8+ T cells adapt to increased lipid concentrations by increasing expression of the scavenger receptor CD36. This, in turn, leads to intracellular accumulation of oxidized lipid and T cell dysfunction downstream of lipid peroxidation.
Depleting regulatory T cells (T
cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to ...systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral T
cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral T
cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming T
cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in T
cells suppressed tumor growth accompanied by a decrease in intratumoral T
cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral T
cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.
It is being increasingly acknowledged that immune cells depend on certain metabolic traits to perform their functions and that the extracellular environment can influence cell metabolism and vice ...versa. Dendritic cell (DC) subsets traffic through highly diverse environments from the bone marrow, where they develop, to the various peripheral tissues, where they differentiate and capture antigens, before they migrate to the lymph node to present antigens and prime T cells. It is plausible that DC subsets modulate their stimulatory abilities in response to unique metabolic programming. The metabolic requirements of DCs are just recently being discovered, and subset- and context-specific metabolic phenotypes in DCs are highly intertwined with DC functions. In this review, we present the current knowledge on the intrinsic and extrinsic determinants of DC metabolism, how they regulate DC function with examples from tumor biology and in interaction with the microbiota, and discuss how this can be applied therapeutically.
PDF
