Nrf2 in TIME: The Emerging Role of Nuclear Factor Erythroid 2-Related Factor 2 in the Tumor Immune Microenvironment

Nuclear factor erythroid 2-related factor 2 (Nrf2) mediates the cellular antioxidant response, allowing adaptation and survival under conditions of oxidative, electrophilic and inflammatory stress, and has a role in metabolism, inflammation and immunity. Activation of Nrf2 provides broad and long-lasting cytoprotection, and is often hijacked by cancer cells, allowing their survival under unfavorable conditions. Moreover, Nrf2 activation in established human tumors is associated with resistance to chemo-, radio-, and immunotherapies. In addition to cancer cells, Nrf2 activation can also occur in tumor-associated macrophages (TAMs) and facilitate an anti-inflammatory, immunosuppressive tumor immune microenvironment (TIME). Several cancer cell-derived metabolites, such as itaconate, L-kynurenine, lactic acid and hyaluronic acid, play an important role in modulating the TIME and tumor-TAMs crosstalk, and have been shown to activate Nrf2. The effects of Nrf2 in TIME are context-depended, and involve multiple mechanisms, including suppression of pro-inflammatory cytokines, increased expression of programmed cell death ligand 1 (PD-L1), macrophage colony-stimulating factor (M-CSF) and kynureninase, accelerated catabolism of cytotoxic labile heme, and facilitating the metabolic adaptation of TAMs. This understanding presents both challenges and opportunities for strategic targeting of Nrf2 in cancer.

[1]  K. Flaherty,et al.  Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth. , 2022, Nature metabolism.

[2]  T. Kensler,et al.  Novel NRF2‐activated cancer treatments utilizing synthetic lethality , 2022, IUBMB life.

[3]  Hongying Chen,et al.  Indoleamine 2,3-dioxygenase mediates the therapeutic effects of adipose-derived stromal/stem cells in experimental periodontitis by modulating macrophages through the kynurenine-AhR-NRF2 pathway , 2022, Molecular metabolism.

[4]  S. Kusmartsev,et al.  Deregulated hyaluronan metabolism in the tumor microenvironment drives cancer inflammation and tumor-associated immune suppression , 2022, Frontiers in Immunology.

[5]  J. van Grevenynghe,et al.  Regulation of innate immunity by Nrf2. , 2022, Current opinion in immunology.

[6]  Roland Bruderer,et al.  DIA label-free proteomic analysis of murine bone-marrow-derived macrophages , 2022, STAR protocols.

[7]  N. Putluri,et al.  Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response , 2022, Journal for ImmunoTherapy of Cancer.

[8]  In-geun Ryoo,et al.  High Levels of Hyaluronic Acid Synthase-2 Mediate NRF2-Driven Chemoresistance in Breast Cancer Cells , 2022, Biomolecules & therapeutics.

[9]  K. Büssow,et al.  Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism , 2022, Nature Metabolism.

[10]  Jennifer B Dennison,et al.  Mutational Activation of the NRF2 Pathway Upregulates Kynureninase Resulting in Tumor Immunosuppression and Poor Outcome in Lung Adenocarcinoma , 2022, Cancers.

[11]  Alireza Rezaiemanesh,et al.  HRD1 in human malignant neoplasms: Molecular mechanisms and novel therapeutic strategy for cancer. , 2022, Life sciences.

[12]  Xue Zhang,et al.  Immune response gene 1 deficiency impairs Nrf2 activation and aggravates liver fibrosis in mice. , 2022, Biochemical and biophysical research communications.

[13]  T. Köcher,et al.  Kynurenine importation by SLC7A11 propagates anti-ferroptotic signaling. , 2022, Molecular cell.

[14]  Dean P. Jones,et al.  Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology , 2022, Nature Reviews Molecular Cell Biology.

[15]  Shaoshan Hu,et al.  Blocking iASPP/Nrf2/M-CSF axis improves anti-cancer effect of chemotherapy-induced senescence by attenuating M2 polarization , 2022, Cell Death & Disease.

[16]  G. Kato,et al.  Immunomodulatory actions of a kynurenine-derived endogenous electrophile , 2022, bioRxiv.

[17]  L. O’Neill,et al.  The role of itaconate in host defense and inflammation , 2022, The Journal of clinical investigation.

[18]  A. Lamond,et al.  Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response , 2022, iScience.

[19]  L. Torrente,et al.  Targeting NRF2 and Its Downstream Processes: Opportunities and Challenges. , 2021, Annual review of pharmacology and toxicology.

[20]  D. Goyary,et al.  Exploring the frostbite healing potential of hyaluronic acid based hydrogel of Manuka honey through in-silico antithrombotic and anti-platelet studies of major phytoconstituents and in-vivo evaluation in Wistar rat model , 2021, Drug development and industrial pharmacy.

[21]  Y. Surh,et al.  The Enhanced Inhibitory Effect of Estrogen on PD-L1 Expression Following Nrf2 Deficiency in the AOM/DSS Model of Colitis-Associated Cancer , 2021, Frontiers in Oncology.

[22]  D. Greco,et al.  Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential. , 2021, Immunity.

[23]  V. Torri,et al.  Heme catabolism by tumor-associated macrophages controls metastasis formation , 2021, Nature Immunology.

[24]  H. Hirte,et al.  Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment. , 2021, Cell metabolism.

[25]  B. Obermayer,et al.  Single-cell RNA sequencing reveals distinct tumor microenvironmental patterns in lung adenocarcinoma , 2020, bioRxiv.

[26]  F. Gnad,et al.  NRF2 Activation Promotes Aggressive Lung Cancer and Associates with Poor Clinical Outcomes , 2020, Clinical Cancer Research.

[27]  Esben B. Svenningsen,et al.  SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate , 2020, Nature Communications.

[28]  Ping-Chih Ho,et al.  Lactate modulation of immune responses in inflammatory versus tumour microenvironments , 2020, Nature Reviews Immunology.

[29]  Masayuki Yamamoto,et al.  Microenvironmental Activation of Nrf2 Restricts the Progression of Nrf2-Activated Malignant Tumors , 2020, Cancer Research.

[30]  Jiyong Liang,et al.  Upregulation of programmed death ligand 1 by liver kinase B1 and its implication in programmed death 1 blockade therapy in non-small cell lung cancer. , 2020, Life sciences.

[31]  A. Dinkova-Kostova,et al.  KEAP1, a cysteine-based sensor and a drug target for the prevention and treatment of chronic disease , 2020, Open Biology.

[32]  A. Dinkova-Kostova,et al.  Biomarker Exploration in Human Peripheral Blood Mononuclear Cells for Monitoring Sulforaphane Treatment Responses in Autism Spectrum Disorder , 2020, Scientific Reports.

[33]  Dean P. Jones,et al.  Reactive oxygen species (ROS) as pleiotropic physiological signalling agents , 2020, Nature Reviews Molecular Cell Biology.

[34]  R. Hamanaka,et al.  Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response , 2020, bioRxiv.

[35]  Junsong Wang,et al.  4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects , 2019, Nature Communications.

[36]  S. Ostrand-Rosenberg,et al.  Survival of the fittest: how myeloid-derived suppressor cells survive in the inhospitable tumor microenvironment , 2019, Cancer Immunology, Immunotherapy.

[37]  A. Thielke,et al.  Nrf2 Negatively Regulates Type I Interferon Responses and Increases Susceptibility to Herpes Genital Infection in Mice , 2019, Front. Immunol..

[38]  P. Magistretti,et al.  Lactate and pyruvate promote oxidative stress resistance through hormetic ROS signaling , 2019, Cell Death & Disease.

[39]  M. Turner,et al.  Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression. , 2019, Cell metabolism.

[40]  Antonio Cuadrado,et al.  Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases , 2019, Nature Reviews Drug Discovery.

[41]  E. Andrechek,et al.  Identification of an Unfavorable Immune Signature in Advanced Lung Tumors from Nrf2-Deficient Mice. , 2018, Antioxidants & redox signaling.

[42]  Y. Morine,et al.  Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction , 2018, Cell Communication and Signaling.

[43]  M. Nyegaard,et al.  Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming , 2018, Nature Communications.

[44]  J. Weiss,et al.  Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors , 2018, The Journal of clinical investigation.

[45]  Donna D. Zhang,et al.  NRF2 and the Hallmarks of Cancer. , 2018, Cancer cell.

[46]  Masayuki Yamamoto,et al.  The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. , 2018, Physiological reviews.

[47]  D. Wang,et al.  MicroRNA-378 acts as a prognosis marker and inhibits cell migration, invasion and epithelial-mesenchymal transition in human glioma by targeting IRG1. , 2018, European review for medical and pharmacological sciences.

[48]  K. Itoh,et al.  C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape , 2018, Scientific Reports.

[49]  Rutao Cui,et al.  Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy , 2018, Oncogene.

[50]  In-geun Ryoo,et al.  High CD44 expression mediates p62-associated NFE2L2/NRF2 activation in breast cancer stem cell-like cells: Implications for cancer stem cell resistance , 2018, Redox biology.

[51]  Matthew E. Ritchie,et al.  Synergy between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small-Cell Lung Cancer with an Altered Immune Microenvironment. , 2018, Cell metabolism.

[52]  Edward T Chouchani,et al.  Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1 , 2018, Nature.

[53]  J. Hayes,et al.  A partnership with the proteasome; the destructive nature of GSK3 , 2018, Biochemical pharmacology.

[54]  A. Kriegstein,et al.  Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment , 2017, Genome Biology.

[55]  J. Liu,et al.  Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor , 2017, Nature Immunology.

[56]  M. V. Vander Heiden,et al.  Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer , 2017, eLife.

[57]  J. Hiscott,et al.  Activation of Nrf2 Signaling Augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[58]  D. Quail,et al.  The Microenvironmental Landscape of Brain Tumors. , 2017, Cancer cell.

[59]  M. Kolb,et al.  M2‐polarized and tumor‐associated macrophages alter NK cell phenotype and function in a contact‐dependent manner , 2017, Journal of leukocyte biology.

[60]  K. Nakayama,et al.  Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription , 2016, Nature Communications.

[61]  T. Shibata,et al.  NRF2 Intensifies Host Defense Systems to Prevent Lung Carcinogenesis, but After Tumor Initiation Accelerates Malignant Cell Growth. , 2016, Cancer research.

[62]  O. Harismendy,et al.  Nrf2 Induces IL-17D to Mediate Tumor and Virus Surveillance. , 2016, Cell reports.

[63]  S. Ryter,et al.  IRG1 induced by heme oxygenase-1/carbon monoxide inhibits LPS-mediated sepsis and pro-inflammatory cytokine production , 2015, Cellular and Molecular Immunology.

[64]  R. Medzhitov,et al.  Tissue biology perspective on macrophages , 2015, Nature Immunology.

[65]  F. Ginhoux,et al.  New insights into the multidimensional concept of macrophage ontogeny, activation and function , 2015, Nature Immunology.

[66]  Kathryn E. Crosier,et al.  An inducible transgene reports activation of macrophages in live zebrafish larvae. , 2015, Developmental and comparative immunology.

[67]  T. Teramura,et al.  Hyaluronic acid regulates a key redox control factor Nrf2 via phosphorylation of Akt in bovine articular chondrocytes , 2015, FEBS open bio.

[68]  T. Wurdinger,et al.  Mechanisms of intimate and long-distance cross-talk between glioma and myeloid cells: how to break a vicious cycle. , 2014, Biochimica et biophysica acta.

[69]  Shizhong Zhang,et al.  Immune responsive gene 1, a novel oncogene, increases the growth and tumorigenicity of glioma. , 2014, Oncology reports.

[70]  G. Prendergast,et al.  Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer , 2014, Cancer Immunology, Immunotherapy.

[71]  J. Hayes,et al.  The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. , 2014, Trends in biochemical sciences.

[72]  T. Nakajima,et al.  Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis , 2014, Genes & development.

[73]  P. Storz.  Oxidative Stress in Cancer , 2013 .

[74]  R. Balling,et al.  Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production , 2013, Proceedings of the National Academy of Sciences.

[75]  A. Cuadrado,et al.  Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. , 2012, Oncogene.

[76]  M. Sporn,et al.  Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease , 2012, Pharmacological Reviews.

[77]  Tsonwin Hai,et al.  ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression , 2011, Nature Medicine.

[78]  Charles D Mills,et al.  M1 and M2 Macrophages: Oracles of Health and Disease. , 2012, Critical reviews in immunology.

[79]  S. Reddy,et al.  Enhancing Nrf2 pathway by disruption of Keap1 in myeloid leukocytes protects against sepsis. , 2011, American journal of respiratory and critical care medicine.

[80]  Wenyun Lu,et al.  Itaconic acid is a mammalian metabolite induced during macrophage activation. , 2011, Journal of the American Chemical Society.

[81]  L. Yarmus,et al.  Targeting Nrf2 Signaling Improves Bacterial Clearance by Alveolar Macrophages in Patients with COPD and in a Mouse Model , 2011, Science Translational Medicine.

[82]  P. Rada,et al.  SCF/β-TrCP Promotes Glycogen Synthase Kinase 3-Dependent Degradation of the Nrf2 Transcription Factor in a Keap1-Independent Manner , 2011, Molecular and Cellular Biology.

[83]  M. McMahon,et al.  Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals , 2010, Proceedings of the National Academy of Sciences.

[84]  V. Raman,et al.  Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung. , 2010, Carcinogenesis.

[85]  Biswal,et al.  NADPH Oxidase-Dependent Reactive Oxygen Species Mediate Amplified TLR4 Signaling and Sepsis-Induced Mortality in Nrf2-Deficient Mice , 2010, The Journal of Immunology.

[86]  Mihee M. Kim,et al.  The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1 , 2010, Nature Cell Biology.

[87]  Amanda Doucette,et al.  An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer , 2009, Nature.

[88]  J. Edwards,et al.  Exploring the full spectrum of macrophage activation , 2008, Nature Reviews Immunology.

[89]  A. Dinkova-Kostova,et al.  Coordinate regulation of enzyme markers for inflammation and for protection against oxidants and electrophiles , 2008, Proceedings of the National Academy of Sciences.

[90]  J. Kuratsu,et al.  Possible involvement of the M2 anti‐inflammatory macrophage phenotype in growth of human gliomas , 2008, The Journal of pathology.

[91]  K. Itoh,et al.  Nrf2 regulates the alternative first exons of CD36 in macrophages through specific antioxidant response elements. , 2008, Archives of biochemistry and biophysics.

[92]  M. Sporn,et al.  Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. , 2007, Antioxidants & redox signaling.

[93]  S. Yokoyama,et al.  Different Electrostatic Potentials Define ETGE and DLG Motifs as Hinge and Latch in Oxidative Stress Response , 2007, Molecular and Cellular Biology.

[94]  K. Itoh,et al.  Dimerization of Substrate Adaptors Can Facilitate Cullin-mediated Ubiquitylation of Proteins by a “Tethering” Mechanism , 2006, Journal of Biological Chemistry.

[95]  Young-Myeong Kim,et al.  3-Hydroxyanthranilic acid, one of L-tryptophan metabolites, inhibits monocyte chemoattractant protein-1 secretion and vascular cell adhesion molecule-1 expression via heme oxygenase-1 induction in human umbilical vein endothelial cells. , 2006, Atherosclerosis.

[96]  Masayuki Yamamoto,et al.  Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. , 2006, The Journal of clinical investigation.

[97]  P. Valentin-Weigand,et al.  Mycobacterium paratuberculosis, Mycobacterium smegmatis, and lipopolysaccharide induce different transcriptional and post‐transcriptional regulation of the IRG1 gene in murine macrophages , 2006, Journal of leukocyte biology.

[98]  D. Kuhn,et al.  Gene expression profile of activated microglia under conditions associated with dopamine neuronal damage , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[99]  Paul Talalay,et al.  Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[100]  B. Toole,et al.  Hyaluronan: from extracellular glue to pericellular cue , 2004, Nature Reviews Cancer.

[101]  J. Morrow,et al.  Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products. , 2004, The Biochemical journal.

[102]  K. Itoh,et al.  Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Delta(12,14)-prostaglandin j(2). , 2004, Molecular and cellular biology.

[103]  Mark Hannink,et al.  Distinct Cysteine Residues in Keap1 Are Required for Keap1-Dependent Ubiquitination of Nrf2 and for Stabilization of Nrf2 by Chemopreventive Agents and Oxidative Stress , 2003, Molecular and Cellular Biology.

[104]  R. Cole,et al.  Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[105]  Ken Itoh,et al.  Transcription Factor Nrf2 Coordinately Regulates a Group of Oxidative Stress-inducible Genes in Macrophages* , 2000, The Journal of Biological Chemistry.

[106]  K. Itoh,et al.  An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. , 1997, Biochemical and biophysical research communications.

[107]  A. Choi,et al.  Parallel Induction of Heme Oxygenase-1 and Chemoprotective Phase 2 Enzymes by Electrophiles and Antioxidants: Regulation by Upstream Antioxidant-Responsive Elements (ARE) , 1995, Molecular medicine.