Immunometabolism in cancer at a glance

ABSTRACT The scientific knowledge about tumor metabolism has grown at a fascinating rate in recent decades. We now know that tumors are highly active both in their metabolism of available nutrients and in the secretion of metabolic by-products. However, cancer cells can modulate metabolic pathways and thus adapt to specific nutrients. Unlike tumor cells, immune cells are not subject to a ‘micro-evolution’ that would allow them to adapt to progressing tumors that continuously develop new mechanisms of immune escape. Consequently, immune cells are often irreversibly affected and may allow or even support cancer progression. The mechanisms of how tumors change immune cell function are not sufficiently explored. It is, however, clear that commonly shared features of tumor metabolism, such as local nutrient depletion or production of metabolic ‘waste’ can broadly affect immune cells and contribute to immune evasion. Moreover, immune cells utilize different metabolic programs based on their subtype and function, and these immunometabolic pathways can be modified in the tumor microenvironment. In this review and accompanying poster, we identify and describe the common mechanisms by which tumors metabolically affect the tumor-infiltrating cells of native and adaptive immunity, and discuss how these mechanisms may lead to novel therapeutic opportunities. Summary: This ‘At a Glance’ review and accompanying poster address how tumors can negatively affect immune cells through depletion of critical nutrients or through production of toxic metabolic products.

[1]  R. Davis,et al.  Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy. , 2018, Cell metabolism.

[2]  A. Neff,et al.  Comparative metabolic analysis in head and neck cancer and the normal gingiva , 2018, Clinical Oral Investigations.

[3]  M. Smyth,et al.  Targeting immunosuppressive adenosine in cancer , 2017, Nature Reviews Cancer.

[4]  David K. Finlay,et al.  Srebp-controlled glucose metabolism is essential for NK cell functional responses , 2017, Nature Immunology.

[5]  Liqin Zheng,et al.  Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells , 2017, Oncoimmunology.

[6]  Marc Hennequart,et al.  Constitutive IDO1 Expression in Human Tumors Is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance , 2017, Cancer Immunology Research.

[7]  Kristie L. Rose,et al.  Critical role of SIK3 in mediating high salt and IL-17 synergy leading to breast cancer cell proliferation , 2017, PloS one.

[8]  W. Rathmell,et al.  Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. , 2017, JCI insight.

[9]  V. Tiriveedhi,et al.  Inflammatory role of high salt level in tumor microenvironment (Review). , 2017, International journal of oncology.

[10]  David K. Finlay,et al.  What Fuels Natural Killers? Metabolism and NK Cell Responses , 2017, Front. Immunol..

[11]  E. Tagliabue,et al.  Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation. , 2017, Seminars in cancer biology.

[12]  Zhi-Yao He,et al.  Simultaneous enhancement of cellular and humoral immunity by the high salt formulation of Al(OH)3 adjuvant , 2017, Cell Research.

[13]  J. Yu,et al.  Interplay between epigenetics and metabolism in oncogenesis: mechanisms and therapeutic approaches , 2017, Oncogene.

[14]  J. Woodgett,et al.  GSK3 is a metabolic checkpoint regulator in B cells , 2016, Nature Immunology.

[15]  S. Haferkamp,et al.  LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. , 2016, Cell metabolism.

[16]  P. Carmeliet,et al.  Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and Metastasis. , 2016, Cell metabolism.

[17]  P. Massion,et al.  Fluorescence-based measurement of cystine uptake through xCT shows requirement for ROS detoxification in activated lymphocytes. , 2016, Journal of immunological methods.

[18]  M. Warmoes,et al.  Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression , 2016, Nature Immunology.

[19]  J. Rathmell,et al.  Nutrients and the microenvironment to feed a T cell army. , 2016, Seminars in immunology.

[20]  S. Hanash,et al.  The Emerging Role of B Cells in Tumor Immunity. , 2016, Cancer research.

[21]  M. Mann,et al.  L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity , 2016, Cell.

[22]  W. Linehan,et al.  Ionic immune suppression within the tumour microenvironment limits T cell effector function , 2016, Nature.

[23]  Deborah S. Barkauskas,et al.  Co-inhibition of CD73 and A2AR Adenosine Signaling Improves Anti-tumor Immune Responses. , 2016, Cancer cell.

[24]  G. Thomas,et al.  Upregulated Glucose Metabolism Correlates Inversely with CD8+ T-cell Infiltration and Survival in Squamous Cell Carcinoma. , 2016, Cancer research.

[25]  A. Richardson,et al.  Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine , 2016, Cell.

[26]  Marcus Schmidt,et al.  Feasibility of induced metabolic bioluminescence imaging in advanced ovarian cancer patients: first results of a pilot study , 2016, Journal of Cancer Research and Clinical Oncology.

[27]  P. Oefner,et al.  Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells , 2016, Oncoimmunology.

[28]  V. Tiriveedhi,et al.  Oleanolic Acid Inhibits High Salt-Induced Exaggeration of Warburg-like Metabolism in Breast Cancer Cells , 2016, Cell Biochemistry and Biophysics.

[29]  R. Gillies,et al.  Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy. , 2016, Cancer research.

[30]  Ping-Chih Ho,et al.  Metabolic communication in tumors: a new layer of immunoregulation for immune evasion , 2016, Journal of Immunotherapy for Cancer.

[31]  D. Hafler,et al.  Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. , 2015, The Journal of clinical investigation.

[32]  Caitlyn E. Bowman,et al.  Preventing Allograft Rejection by Targeting Immune Metabolism. , 2015, Cell reports.

[33]  Philippe A. Robert,et al.  Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation , 2015, Science Signaling.

[34]  V. De Rosa,et al.  Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants , 2015, Nature Immunology.

[35]  R. Schreiber,et al.  Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression , 2015, Cell.

[36]  J. Locasale,et al.  Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses , 2015, Cell.

[37]  P. Oefner,et al.  Metabolic plasticity of human T cells: Preserved cytokine production under glucose deprivation or mitochondrial restriction, but 2‐deoxy‐glucose affects effector functions , 2015, European journal of immunology.

[38]  M. Buck,et al.  T cell metabolism drives immunity , 2015, The Journal of experimental medicine.

[39]  M. Bui,et al.  A phase-1/2 study of adenovirus-p53 transduced dendritic cell vaccine in combination with indoximod in metastatic solid tumors and invasive breast cancer , 2015, Oncotarget.

[40]  F. D’Acquisto,et al.  Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions , 2015, PLoS biology.

[41]  Juan R. Cubillos-Ruiz,et al.  ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis , 2015, Cell.

[42]  A. Oxenius,et al.  The protein LEM promotes CD8+ T cell immunity through effects on mitochondrial respiration , 2015, Science.

[43]  Jeremy J. W. Chen,et al.  Opposite Effects of M1 and M2 Macrophage Subtypes on Lung Cancer Progression , 2015, Scientific Reports.

[44]  J. Rathmell,et al.  T cell metabolic fitness in antitumor immunity. , 2015, Trends in immunology.

[45]  David K. Finlay,et al.  mTORC1-Dependent Metabolic Reprogramming Is a Prerequisite for NK Cell Effector Function , 2014, The Journal of Immunology.

[46]  M. Smyth,et al.  Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. , 2014, Cancer research.

[47]  G. Cline,et al.  Functional polarization of tumour-associated macrophages by tumour-derived lactic acid , 2014, Nature.

[48]  J. Rathmell,et al.  The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. , 2014, Cell metabolism.

[49]  E. Gilson,et al.  The metabolic checkpoint kinase mTOR is essential for interleukin-15 signaling during NK cell development and activation , 2014, Nature Immunology.

[50]  Jae-Hoon Chang,et al.  Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. , 2014, Immunity.

[51]  D. Green,et al.  Metabolic Reprogramming Is Required for Antibody Production That Is Suppressed in Anergic but Exaggerated in Chronically BAFF-Exposed B Cells , 2014, The Journal of Immunology.

[52]  S. Gordon,et al.  The M1 and M2 paradigm of macrophage activation: time for reassessment , 2014, F1000prime reports.

[53]  M. Mazzone,et al.  Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. , 2013, Cancer cell.

[54]  Sung Soo Kim,et al.  Cancer cell metabolism: implications for therapeutic targets , 2013, Experimental & Molecular Medicine.

[55]  T. Maeda,et al.  Acidic extracellular microenvironment and cancer , 2013, Cancer Cell International.

[56]  M. Smyth,et al.  Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors , 2013, Proceedings of the National Academy of Sciences.

[57]  B. Faubert,et al.  Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis , 2013, Cell.

[58]  J. Rathmell,et al.  Metabolic regulation of T lymphocytes. , 2013, Annual review of immunology.

[59]  J. Licht,et al.  Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. , 2013, Immunity.

[60]  A. Regev,et al.  Induction of pathogenic Th17 cells by inducible salt sensing kinase SGK1 , 2013, Nature.

[61]  Linda V. Sinclair,et al.  Antigen receptor control of amino acid transport coordinates the metabolic re-programming that is essential for T cell differentiation , 2013, Nature immunology.

[62]  Bin Hu,et al.  Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c‐Jun activation , 2012, International journal of cancer.

[63]  I. Melero,et al.  A Phase I Pharmacologic Study of Necitumumab (imc-11f8), a Fully Human Igg1 Monoclonal Antibody the Hif-1␣ Hypoxia Response in Tumor-infi Ltrating T Lymphocytes Induces Functional Cd137 (4-1bb) for Immunotherapy , 2022 .

[64]  Hui Yang,et al.  Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. , 2012, Genes & development.

[65]  Wei Gu,et al.  Tumor Suppression in the Absence of p53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence , 2012, Cell.

[66]  C. Uyttenhove,et al.  Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase , 2012, Proceedings of the National Academy of Sciences.

[67]  Pal Pacher,et al.  Adenosine promotes alternative macrophage activation via A2A and A2B receptors , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[68]  M. Weller,et al.  An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor , 2011, Nature.

[69]  G. Semenza,et al.  Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1 , 2011, Cell.

[70]  M. Godejohann,et al.  Metabolomics of B to plasma cell differentiation. , 2011, Journal of proteome research.

[71]  K. Klotz,et al.  Ectonucleotidases CD39 and CD73 on OvCA cells are potent adenosine-generating enzymes responsible for adenosine receptor 2A-dependent suppression of T cell function and NK cell cytotoxicity , 2011, Cancer Immunology, Immunotherapy.

[72]  S. Jakobsen,et al.  Inhibition of tumor lactate oxidation: consequences for the tumor microenvironment. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[73]  B. Seliger,et al.  Warburg phenotype in renal cell carcinoma: High expression of glucose‐transporter 1 (GLUT‐1) correlates with low CD8+ T‐cell infiltration in the tumor , 2011, International journal of cancer.

[74]  J. Rathmell,et al.  Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets , 2011, The Journal of Immunology.

[75]  J. Fechner,et al.  An Interaction between Kynurenine and the Aryl Hydrocarbon Receptor Can Generate Regulatory T Cells , 2010, The Journal of Immunology.

[76]  G. Semenza,et al.  Differentiation Stage-Specific Requirement in Hypoxia-Inducible Factor-1α–Regulated Glycolytic Pathway during Murine B Cell Development in Bone Marrow , 2009, The Journal of Immunology.

[77]  C. MacKenzie,et al.  Antimicrobial and immunoregulatory properties of human tryptophan 2,3‐dioxygenase , 2009, European journal of immunology.

[78]  Mark S. Sundrud,et al.  Halofuginone Inhibits TH17 Cell Differentiation by Activating the Amino Acid Starvation Response , 2009, Science.

[79]  Jennifer E. Van Eyk,et al.  c-Myc suppression of miR-23 enhances mitochondrial glutaminase and glutamine metabolism , 2016 .

[80]  D. Mougiakakos,et al.  Transduction with the Antioxidant Enzyme Catalase Protects Human T Cells against Oxidative Stress1 , 2008, The Journal of Immunology.

[81]  Anthony Mancuso,et al.  Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction , 2008, Proceedings of the National Academy of Sciences.

[82]  T. Gajewski,et al.  Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells , 2008, European journal of immunology.

[83]  J. Mora,et al.  Vitamin effects on the immune system: vitamins A and D take centre stage , 2008, Nature Reviews Immunology.

[84]  Silvia Maggini,et al.  Contribution of Selected Vitamins and Trace Elements to Immune Function , 2007, Annals of Nutrition and Metabolism.

[85]  Gregor Rothe,et al.  Inhibitory effect of tumor cell-derived lactic acid on human T cells. , 2007, Blood.

[86]  T. Gallart,et al.  Role of glutamate on T-cell mediated immunity , 2007, Journal of Neuroimmunology.

[87]  D. Quiceno,et al.  L-arginine availability regulates T-lymphocyte cell-cycle progression. , 2007, Blood.

[88]  F. Ciruela,et al.  Glutamate Released by Dendritic Cells as a Novel Modulator of T Cell Activation1 , 2006, The Journal of Immunology.

[89]  R. Wenger,et al.  Cutting Edge: Hypoxia-Inducible Factor 1α and Its Activation-Inducible Short Isoform I.1 Negatively Regulate Functions of CD4+ and CD8+ T Lymphocytes , 2006, The Journal of Immunology.

[90]  U. Grohmann,et al.  The Combined Effects of Tryptophan Starvation and Tryptophan Catabolites Down-Regulate T Cell Receptor ζ-Chain and Induce a Regulatory Phenotype in Naive T Cells1 , 2006, The Journal of Immunology.

[91]  G. Semenza,et al.  HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. , 2006, Cell metabolism.

[92]  J. Pollard,et al.  Distinct role of macrophages in different tumor microenvironments. , 2006, Cancer research.

[93]  Craig Murdoch,et al.  Macrophage migration and gene expression in response to tumor hypoxia , 2005, International journal of cancer.

[94]  B. Freedman,et al.  Hypoxia inducible factor 1α regulates T cell receptor signal transduction , 2005 .

[95]  B. Baban,et al.  GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. , 2005, Immunity.

[96]  F. Ciruela,et al.  Group I Metabotropic Glutamate Receptors Mediate a Dual Role of Glutamate in T Cell Activation* , 2004, Journal of Biological Chemistry.

[97]  S. Tsugane,et al.  Salt and salted food intake and subsequent risk of gastric cancer among middle-aged Japanese men and women , 2004, British Journal of Cancer.

[98]  S. Saccani,et al.  Regulation of the Chemokine Receptor CXCR4 by Hypoxia , 2003, The Journal of experimental medicine.

[99]  C. Uyttenhove,et al.  Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase , 2003, Nature Medicine.

[100]  C. Lewis,et al.  Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. , 2003, The American journal of pathology.

[101]  S. Colgan,et al.  Ecto-5'-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. , 2002, The Journal of clinical investigation.

[102]  C. Thompson,et al.  The CD28 signaling pathway regulates glucose metabolism. , 2002, Immunity.

[103]  A. Ohta,et al.  Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage , 2001, Nature.

[104]  W. Sly,et al.  Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. , 2001, The American journal of pathology.

[105]  W. Kreutz,et al.  Acidic pH inhibits non-MHC-restricted killer cell functions. , 2000, Clinical immunology.

[106]  W. Kreutz,et al.  An Acidic Microenvironment Inhibits Antitumoral Non–Major Histocompatibility Complex-Restricted Cytotoxicity: Implications for Cancer Immunotherapy , 2000, Journal of immunotherapy.

[107]  W. Kreutz,et al.  An acidic microenvironment impairs the generation of non‐major histocompatibility complex‐restricted killer cells , 2000, Immunology.

[108]  Steve Huang,et al.  Role of A2a Extracellular Adenosine Receptor-Mediated Signaling in Adenosine-Mediated Inhibition of T-Cell Activation and Expansion , 1997 .

[109]  J. Blay,et al.  The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. , 1997, Cancer research.

[110]  G. Semenza,et al.  Hypoxia Response Elements in the Aldolase A, Enolase 1, and Lactate Dehydrogenase A Gene Promoters Contain Essential Binding Sites for Hypoxia-inducible Factor 1* , 1996, The Journal of Biological Chemistry.

[111]  G. Semenza,et al.  Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1 , 1996, Molecular and cellular biology.

[112]  P. Anderson,et al.  Hydrogen peroxide secreted by tumor‐derived macrophages down‐modulates signal‐transducing zeta molecules and inhibits tumor‐specific T cell‐and natural killer cell‐mediated cytotoxicity , 1996, European journal of immunology.

[113]  J. Crawford,et al.  The essential role of L‐glutamine in lymphocyte differentiation in vitro , 1985, Journal of cellular physiology.

[114]  Otto Warburn,et al.  THE METABOLISM OF TUMORS , 1931 .

[115]  O. Warburg,et al.  THE METABOLISM OF TUMORS IN THE BODY , 1927, The Journal of general physiology.

[116]  Marc Hennequart,et al.  Constitutive IDO1 Expression in Human Tumors Is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance. , 2017, Cancer immunology research.

[117]  Benjamin G. Gowen,et al.  Recognition of tumors by the innate immune system and natural killer cells. , 2014, Advances in immunology.

[118]  S. Colgan,et al.  Central role of Sp1-regulated CD39 in hypoxia/ischemia protection. , 2009, Blood.

[119]  H. Arimochi,et al.  High salt culture conditions suppress proliferation of rat C6 glioma cell by arresting cell-cycle progression at S-phase , 2007, Journal of Molecular Neuroscience.

[120]  M. Dewhirst,et al.  Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. , 2001, International journal of radiation oncology, biology, physics.

[121]  Wei Liu,et al.  Distinct involvement of NF‐κB and p38 mitogen‐activated protein kinase pathways in serum deprivation‐mediated stimulation of inducible nitric oxide synthase and its inhibition by 4‐hydroxynonenal , 2001, Journal of cellular biochemistry.