WhatWhat youyou needneed toto knowknow aboutabout innateinnate immunityimmunity
JenniferJennifer KoKo MD,MD, PhDPhD ClevelandCleveland ClinicClinic Immunology/PathologyImmunology/Pathology andand LaboratoryLaboratory MedicineMedicine InnateInnate ImmunityImmunity
FirstFirst lineline ofof defense,defense, immediateimmediate defensedefense DayDay toto dayday protectionprotection OnlyOnly whenwhen innateinnate defensedefense bypassed,bypassed, evadedevaded oror overwhelmedoverwhelmed isis adaptiveadaptive immunityimmunity requiredrequired NonNon--specificspecific RecognizeRecognize pathogenspathogens inin aa genericgeneric wayway DoesDoes notnot conferconfer longlong lastinglasting oror protectiveprotective immunityimmunity toto hosthost EvolutionarilyEvolutionarily older,older, foundfound inin primitiveprimitive organismsorganisms
InnateInnate ImmunityImmunity andand InflammationInflammation
1)1) RespondRespond rapidlyrapidly toto tissuetissue damagedamage physicalphysical andand chemicalchemical barrierbarrier recruitmentrecruitment ofof immuneimmune cellscells toto sitesite ofof injuryinjury 2)2) LimitLimit spreadspread ofof infectioninfection identificationidentification andand removalremoval ofof foreignforeign substancessubstances activationactivation ofof thethe complementcomplement cascadecascade activationactivation ofof coagulationcoagulation cascadecascade 3)3) InitiateInitiate adaptiveadaptive immuneimmune responseresponse antigenantigen presentationpresentation andand cytokinecytokine productionproduction 4)4) InitiateInitiate tissuetissue repairrepair InnateInnate ImmunityImmunity –– Physical/ChemicalPhysical/Chemical BarriersBarriers Breach of physical barrier -“resting” innate immune cells become activated to kill microbes, secrete cytokines to recruit and activate additional leukocytes, and to promote systemic killing and removal of microbes. InnateInnate ImmunityImmunity-- 11stst respondersresponders InnateInnate ImmunityImmunity-- Monocytes/MacrophagesMonocytes/Macrophages
- MonocyteMonocyte --derivedderived macrophagesmacrophages ““largelarge eaterseaters ”” oror histiocytes,histiocytes, areare presentpresent inin allall tissuestissues - ““SentinelsSentinels ”” ofof immuneimmune systemsystem -- surveysurvey forfor ““foreignforeign ”” invadersinvaders - ForeignForeign microbesmicrobes areare recognizedrecognized viavia variousvarious cellcell surfacesurface andand intracellularintracellular receptorsreceptors - ReceptorReceptor ligationligation andand cytokinescytokines causescauses macrophagemacrophage activationactivation - ActivatedActivated macrophagesmacrophages - Digest and present antigens from microbes - Produce chemokines, cytokines, other molecules to recruit other immune cells MacrophageMacrophage PhagocytosisPhagocytosis
Microbe killing= •Phagosome + lysosome = phagolysosome
•Nitric oxide (nitric oxide synthase, iNOS2)
•Superoxide anion (NADPH oxidase, -Macrophages kill respiratory internalized microbes burst)
via reactive oxygen and •Hydrogen nitrogen species peroxide (superoxide dismutase) Phagocyte Toll receptors are stimulated by Pathogen Associated Molecular Patterns (PAMPs) NOD-like receptor (NLR) proteins are intracellular pattern recognition receptors (PRRs) Induced Innate Responses mediated by cytokines secreted by stimulated sentinel cells Chemokines secreted by stimulated sentinel cells recruit additional immune cells InnateInnate ImmunityImmunity--MacrophageMacrophage
Systemic Complement Inflammatory •MBL Cascade Response •TNF α •IL-6 •IL-1 •Pattern Recognition Receptors
•Toll-like receptors •NLRs •Macrophage Phagocytosis mannose receptor (clearance of •Macrophage •Scavenger chemokines/cytokines receptors microbes) •Co-stimulatory molecules •CD80/86 •Neutrophils •TNF α
•IL-8 Recruitment of other cells Cytokine mediated vascular dilation and vascular permeability facilitate neutrophil extravasation into infected tissues
-Macrophage activation causes degradation of membrane phospholipids and rapid production of prostaglandins, leukotrienes and platelet-activating factor which act with cytokines directly on smooth muscle and endothelial cells Cytokine induced adhesion cytokines and chemokines mediate neutrophil weak and firm adhesion to vascular endothelium InnateInnate ImmunityImmunity-- 11stst respondersresponders Neutrophils
Essential to innate immunity, hallmark of acute inflammation Most prevalent WBC in blood with 50-100 billion produced per day 55% bone marrow weight dedicated Migrate in response to IL-8, C5a, leukotrienes, fMLP via chemotaxis Circulate 5.4 days, live in tissue 1-2 days Limit propagation of certain pathogens Limit host damage due to inflammation Phagocytosed by macrophages after pathogen digestion Neutrophil NET formation InnateInnate ImmunityImmunity--MacrophageMacrophage
Systemic Complement Inflammatory •MBL Cascade Response •TNF α •IL-6 •IL-1 •Pattern Recognition Receptors
•Toll-like receptors •NLRs •Macrophage Phagocytosis mannose receptor (clearance of •Macrophage •Scavenger chemokines/cytokines receptors microbes) •Co-stimulatory molecules •CD80/86 •Neutrophils •TNF α
•IL-8 Recruitment NETosis of other cells Cytokines from PAMP-stimulated sentinel cells stimulate the production of acute phase proteins, which opsonize a large spectrum of pathogens bearing common pathogen associated molecular patterns There are two innate mechanisms by which complement can be activated: the lectin pathway and the alternative pathway Complement feeds forward to activate and increase macrophage and neutrophil phagocytosis Complement can form the membrane attack complex, which leads to the lysis of target pathogens The spread of viruses is limited by the interferon response Viral nucleic acids stimulate the production of interferon by the infected cell, which mediates both autocrine and paracrine protective responses InnateInnate ImmunityImmunity-- 11stst respondersresponders NK cells
•Overlap innate and adaptive immunity •Stimulated by Type I interferons •Kill cells with down-regulated MHC I expression •Down-regulated by viruses and tumors trying to avoid CD8+ T-cell killing •Kill “non-self” via mostly shared mechanisms with cytotoxic T-cells •TRAIL •GranzymeB •Perforin InnateInnate ImmunityImmunity andand InflammationInflammation
1)1) RespondRespond rapidlyrapidly toto tissuetissue damagedamage physicalphysical andand chemicalchemical barrierbarrier recruitmentrecruitment ofof immuneimmune cellscells toto sitesite ofof injuryinjury 2)2) LimitLimit spreadspread ofof infectioninfection identificationidentification andand removalremoval ofof foreignforeign substancessubstances activationactivation ofof thethe complementcomplement cascadecascade activationactivation ofof coagulationcoagulation cascadecascade 3)3) InitiateInitiate adaptiveadaptive immuneimmune responseresponse antigenantigen presentationpresentation andand cytokinecytokine productionproduction 4)4) InitiateInitiate tissuetissue repairrepair Adaptive response initiation: Antigen presentation to T cells The context in which macrophage-derived dendritic cells present antigen to T-cells determines the type of adaptive T cell response that follows
ImmuneImmune surveillancesurveillance inin cancercancer CarcinogenCarcinogen--inducedinduced tumorstumors arisearise moremore frequentlyfrequently andand quicklyquickly inin immunodeficientimmunodeficient micemice CancerCancer cellscells thatthat arisearise inin immunodeficientimmunodeficient micemice areare inefficientinefficient atat initiatinginitiating secondarysecondary tumorstumors inin syngeneicsyngeneic immunocompetentimmunocompetent micemice ImmuneImmune surveillancesurveillance inin cancercancer HeavyHeavy CTLCTL andand NKNK cellcell infiltrationinfiltration predictspredicts improvedimproved outcomeoutcome inin severalseveral humanhuman tumorstumors ImmunosuppressedImmunosuppressed organorgan transplanttransplant recipientsrecipients developdevelop donordonor --derivedderived cancercancer fromfrom ostensiblyostensibly tumortumor --freefree donorsdonors ImmuneImmune escapeescape inin cancercancer ClinicallyClinically apparentapparent tumorstumors variablyvariably suppresssuppress thethe antianti --tumortumor immuneimmune responseresponse TumorTumor --associatedassociated inflammationinflammation cancan enhanceenhance tumortumor progressionprogression Immunoediting Normal Cells •Inflammation/radiation/carcinogens/viruses
Transformed Cells Protection •Tumor antigens/peptide-MHC I/ MHCII cross-presentation/NKG2D
3) Escape/Tumor Progression 1) Elimination/Immunosurveillance •T regulatory cells – IL-10 and TGF β •IFN γ and •Tumor-derived cytokines, growth IFN α/β factors, chemokines •Perforin •Trail •Myeloid-derived suppressor •Th1 and T c T cells, NKT, NK, cells (MDSC) γ δT cells 2) Equilibrium/Tumor Persistence
•Genetic instability and immune selection •Tumor variants •Immune exhaustion/inhibition
•Tumors may remain dormant Adapted from Dunn G et al, Nat Rev Immunol 6, 836-48 (2006). ChronicChronic InflammationInflammation hashas aa knownknown rolerole inin cancercancer initiationinitiation
Tobacco,Tobacco, asbestosasbestos BronchialBronchial CACA AlcoholAlcohol HepatocellularHepatocellular CA,CA, GastricGastric CA,CA, PancreaticPancreatic CACA HelicobacterHelicobacter pyloripylori MALTMALT lymphomalymphoma ShistosomaShistosoma bladderbladder CACA HCVHCV HepatocellularHepatocellular CACA HPVHPV CervicalCervical CACA EndogenousEndogenous inflammationinflammation inin inflammatoryinflammatory bowelbowel diseadiseasese ColonColon CACA Barrett'sBarrett's esophagusesophagus EsophagealEsophageal CACA -Scale largely tipped to pro-tumor effect of macrophages in established cancers
nature immunology volume 11 number 10 october 2010 MacrophageMacrophage andand chemotherapychemotherapy
TAMTAM modulatemodulate responsesresponses toto chemotherapychemotherapy MacrophagesMacrophages andand DCsDCs areare knownknown toto mediatemediate ‘‘‘‘ immunogenicimmunogenic cellcell deathdeath ’’’’ (ICD)(ICD) whichwhich somesome chemotherapieschemotherapies induceinduce inin somesome tumortumor modelsmodels release of ‘‘ eat -me ’’ signals (e.g. ATP and high -mobility group B1 [HMGB1]) from dying tumor cells enhanced by some chemotherapies monocyte activation and enhancement of their APC capacity and promotion of T cell responses against immunogenic tumors AntitumorAntitumor activityactivity ofof somesome cytotoxiccytotoxic agentsagents maymay depdependend onon theirtheir abilityability toto reprogramreprogram propro --tumoraltumoral macrophagesmacrophages MacrophageMacrophage andand chemotherapychemotherapy
TAMTAM depletiondepletion (anti(anti --CSF1CSF1 antibodies)antibodies) enhancesenhances thethe efficacyefficacy ofof somesome combinationcombination chemotherapychemotherapy cyclophosphamide, methotrexate, and 5 -fluorouracil in chemoresistant, human breast cancer xenografts in immunodeficient mice Paclitaxel in immunocompetent mice via increased anti -tumor CD8+ T - cell responses when macrophages were depleted MacrophageMacrophage --derivedderived cathepsinscathepsins protectprotect cancercancer cellscells fromfrom thethe directdirect cytotoxiccytotoxic effectseffects ofof severalseveral chemotherapeutichemotherapeuticscs CathepsinB inflammasome IL -1b IL -17 blunted chemo effect MacrophageMacrophage --derivedderived factorsfactors activateactivate STAT3STAT3 inin cancercancer stemstem cellscells toto promotepromote chemoresistancechemoresistance UltimateUltimate effecteffect maymay dependdepend onon tumortumor immunogenicity,immunogenicity, sensitivitysensitivity ofof macrophagesmacrophages toto drug,drug, andand thethe inhereninherentt statestate ofof thth ee macrophagesmacrophages inin thethe particularparticular tumortumor MacrophagesMacrophages initiateinitiate aa woundwound reparativereparative programprogram thatthat enhancesenhances tumortumor regrowthregrowth NeutrophilNeutrophil
Potential Reality
TumorTumor cellcell GenotoxicityGenotoxicity associatedassociated withwith neutrophilneutrophil killingkilling ROSROS maymay initiateinitiate cancercancer throughthrough Neutrophilia,Neutrophilia, andand highhigh reactivereactive neutrophil:lymphocyteneutrophil:lymphocyte (N:L)(N:L) ratioratio oxygenoxygen associatedassociated withwith poorpoor outcomeoutcome inin multiplemultiple species???species??? tumortumor typestypes PromotePromote angiogenesisangiogenesis AntiAnti --tumortumor TT --cellcell suppressionsuppression TumorTumor cellcell migration,migration, invasioninvasion andand metastasismetastasis NK cells
Prevent tumor progression Immunosurveillance Elimination phase Cell stress Non-self (low or absent MHC I) Prevent tumor metastasis Attack tumor emboli in the lungs NK cell tumor targeting can be inhibited by platelets “Pseudo-self” Oncoimmunology. 2012 July 1; 1(4): 557–559. SummarySummary
FunctionFunction ofof InnateInnate ImmunityImmunity 1) Respond rapidly to tissue damage 2) Limit spread of infection 3) Initiate adaptive immune response 4) Initiate tissue repair InnateInnate ImmunityImmunity inin CancerCancer NeutrophilsNeutrophils Promote tumor initiation Promote tumor spread MacrophagesMacrophages Pro and anti - tumor effects in tumor initiation Promote tumor spread NKNK cellscells Inhibit tumor initiation Inhibit tumor spread Questions?Questions? 1) What is the importance of innate immunity in cancer?
A) Innate immunity initiates malignant transformation via neutrophil-derived genotoxic stress B) Innate immunity eradicates transformed tumor cells via NK recognition of non-self or cell stress C) Innate immunity promotes tumor spread via myeloid cell mediated CD8+ T cell inhibition D) Innate immunity promotes tumor spread via angiogenesis upregulation E) All of the above 2) Which of the following is not a function of Macrophages?
A) Phagocytosis and presentation of microbes or tumor- associated antigens to T-cells B) Upregulation of acute phase protein production and systemic inflammatory response C) Extrude a web of fibers composed of chromatin and serine proteases that trap and kill microbes extracellularly D) Promote wound healing through increased angiogenesis E) All of the above are functions 3) Complement cascade can be activated by the lectin pathway and the alternative pathway?
A) True B) False 4) Tumor associated macrophages are mostly M2- polarized, which is desirable for tumor eradication?
A) True B) False 5)Tumor infiltrating neutrophils promote tumor cell invasion and metastasis via matrix metalloproteinases ?
A) True B) False