The Blockade Of Immune Checkpoints In Cancer
REVIEWSThe blockade of immune checkpointsin cancer immunotherapyDrew M. PardollAbstract Among the most promising approaches to activating therapeutic antitumourimmunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora ofinhibitory pathways hardwired into the immune system that are crucial for maintainingself-tolerance and modulating the duration and amplitude of physiological immune responsesin peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumoursco-opt certain immune-checkpoint pathways as a major mechanism of immune resistance,particularly against T cells that are specific for tumour antigens. Because many of the immunecheckpoints are initiated by ligand–receptor interactions, they can be readily blocked byantibodies or modulated by recombinant forms of ligands or receptors. CytotoxicT‑lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class ofimmunotherapeutics to achieve US Food and Drug Administration (FDA) approval.Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such asprogrammed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhanceantitumour immunity with the potential to produce durable clinical responses.AmplitudeIn immunology, this refers tothe level of effector output. ForT cells, this can be levels ofcytokine production,proliferation or target killingpotential.Johns Hopkins UniversitySchool of Medicine, SidneyKimmel ComprehensiveCancer Center, CRB1 Room444, 1650 Orleans Street,Baltimore, Maryland 21287,USAe-mail: dpardol1@jhmi.edudoi:10.1038/nrc3239The myriad of genetic and epigenetic alterations thatare characteristic of all cancers provide a diverse set ofantigens that the immune system can use to distinguishtumour cells from their normal counterparts. In thecase of T cells, the ultimate amplitude and quality ofthe response, which is initiated through antigen recognition by the T cell receptor (TCR), is regulated by a balance between co-stimulatory and inhibitory signals (thatis, immune checkpoints)1,2 (FIG. 1). Under normal physio logical conditions, immune checkpoints are crucial forthe maintenance of self-tolerance (that is, the preventionof autoimmunity) and also to protect tissues from damagewhen the immune system is responding to pathogenicinfection. As described in this Review, the expressionof immune-checkpoint proteins can be dysregulated bytumours as an important immune resistance mechanism. T cells have been the major focus of efforts totherapeutically manipulate endogenous anti tumourimmunity owing to: their capacity for the selective recognition of peptides derived from proteins in all cellularcompartments; their capacity to directly recognize andkill antigen-expressing cells (by CD8 effector T cells; alsoknown as cytotoxic T lymphocytes (CTLs)); and theirability to orchestrate diverse immune responses (byCD4 helper T cells), which integrates adaptive and innateeffector mechanisms. Thus, agonists of co-stimulatoryreceptors or antagonists of inhibitory signals (the subjectof this Review), both of which result in the amplification of antigen-specific T cell responses, are the primaryagents in current clinical testing (TABLE 1). Indeed, theblockade of immune checkpoints seems to unleashthe potential of the antitumour immune response in afashion that is transforming human cancer therapeutics.T cell-mediated immunity includes multiple sequential steps involving the clonal selection of antigenspecific cells, their activation and proliferation in secondary lymphoid tissues, their trafficking to sites of antigenand inflammation, the execution of direct effector functions and the provision of help (through cytokines andmembrane ligands) for a multitude of effector immunecells. Each of these steps is regulated by counterbalancing stimulatory and inhibitory signals that fine-tune theresponse. Although virtually all inhibitory signals inthe immune response ultimately affect intracellular signalling pathways, many are initiated through membranereceptors, the ligands of which are either membranebound or soluble (cytokines). As a general rule, costimulatory and inhibitory receptors and ligands thatregulate T cell activation are not necessarily over expressed in cancers relative to normal tissues, whereasinhibitory ligands and receptors that regulate T cell effector functions in tissues are commonly overexpressed on252 APRIL 2012 VOLUME 12www.nature.com/reviews/cancer 2012 Macmillan Publishers Limited. All rights reserved
F O C U S O N t u m our i m m uno lo g y & i m m unotRhpyE erV I EaWSAt a glance The huge number of genetic and epigenetic changes that are inherent to most cancercells provide plenty of tumour-associated antigens that the host immune system canrecognize, thereby requiring tumours to develop specific immune resistancemechanisms. An important immune resistance mechanism involves immune-inhibitorypathways, termed immune checkpoints, which normally mediate immune toleranceand mitigate collateral tissue damage. A particularly important immune-checkpoint receptor is cytotoxic T‑lymphocyteassociated antigen 4 (CTLA4), which downmodulates the amplitude of T cellactivation. Antibody blockade of CTLA4 in mouse models of cancer inducedantitumour immunity. Clinical studies using antagonistic CTLA4 antibodies demonstrated activity inmelanoma. Despite a high frequency of immune-related toxicity, this therapyenhanced survival in two randomized Phase III trials. Anti‑CTLA4 therapy was the firstagent to demonstrate a survival benefit in patients with advanced melanoma and wasapproved by the US Food and Drug Administration (FDA) in 2010. Some immune-checkpoint receptors, such as programmed cell death protein 1 (PD1),limit T cell effector functions within tissues. By upregulating ligands for PD1, tumourcells block antitumour immune responses in the tumour microenvironment. Early-stage clinical trials suggest that blockade of the PD1 pathway induces sustainedtumour regression in various tumour types. Responses to PD1 blockade may correlatewith the expression of PD1 ligands by tumour cells. Multiple additional immune-checkpoint receptors and ligands, some of which areselectively upregulated in various types of tumour cells, are prime targets forblockade, particularly in combination with approaches that enhance the activation ofantitumour immune responses, such as vaccines.QualityIn immunology, this refers tothe type of immune responsegenerated, which is oftendefined as the pattern ofcytokine production. This, inturn, mediates responsesagainst specific types ofpathogen. For example, CD4 T cells can be predominantly:TH1 cells (characterized by IFNγproduction; these cells areimportant for antiviral andantitumour responses); TH2cells (characterized by IL‑4 andIL‑13 production; these cellsare important for antihelminthresponses); or TH17 cells(characterized by IL‑17 andIL‑22 production; these cellsare important for mucosalbacterial and fungal responses).AutoimmunityImmune responses against anindividual’s normal cells ortissues.CD8 effector T cellsT cells that are characterizedby the expression of CD8. Theyrecognize antigenic peptidespresented by MHC class Imolecules and are able todirectly kill target cells thatexpress the cognate antigen.tumour cells or on non-transformed cells in the tumourmicroenvironment. It is the soluble and membranebound receptor–ligand immune checkpoints that arethe most druggable using agonist antibodies (for costimulatory pathways) or antagonist antibodies (forinhibitory pathways) (TABLE 1). Therefore, in contrast tomost currently approved antibodies for cancer therapy,antibodies that block immune checkpoints do not target tumour cells directly, instead they target lymphocytereceptors or their ligands in order to enhance endogenousantitumour activity.Another category of immune-inhibitory moleculesincludes certain metabolic enzymes, such as indoleamine 2,3‑dioxygenase (IDO) — which is expressed by bothtumour cells and infiltrating myeloid cells — and arginase, which is produced by myeloid-derived suppressor cells3–9. These enzymes inhibit immune responsesthrough the local depletion of amino acids that areessential for anabolic functions in lymphocytes (particularly T cells) or through the synthesis of specific naturalligands for cytosolic receptors that can alter lymphocyte functions. Although this category is not covered inthis Review, these enzymes can be inhibited to enhanceintratumoral inflammation by molecular analogues oftheir substrates that act as competitive inhibitors orsuicide substrates10–12.In considering the mechanisms of action of inhibitors of various immune checkpoints, it is crucial toappreciate the diversity of immune functions that theyregulate. For example, the two immune-checkpointreceptors that have been most actively studied in thecontext of clinical cancer immunotherapy, cytotoxicT‑lymphocyte-associated antigen 4 (CTLA4; alsoknown as CD152) and programmed cell death protein 1(PD1; also known as CD279) — which are both inhibitory receptors — regulate immune responses at different levels and by different mechanisms. The clinicalactivity of antibodies that block either of these receptorsimplies that antitumour immunity can be enhanced atmultiple levels and that combinatorial strategies can beintelligently designed, guided by mechanistic considerations and preclinical models. This Review focuseson the CTLA4 and PD1 pathways because these arethe two immune checkpoints for which clinical information is currently available. However, it is importantto emphasize that multiple additional immune checkpoints represent promising targets for therapeuticblockade based on preclinical experiments, and inhibitors for many of these are under active development(TABLE 1).CTLA4: the godfather of checkpointsThe biology of CTLA4. CTLA4, the first immunecheckpoint receptor to be clinically targeted, is expressedexclusively on T cells where it primarily regulates theamplitude of the early stages of T cell activation.Primarily, CTLA4 counteracts the activity of the T cellco-stimulatory receptor, CD28 (REFS 13–15). CD28does not affect T cell activation unless the TCR is firstengaged by cognate antigen. Once antigen recognitionoccurs, CD28 signalling strongly amplifies TCR signalling to activate T cells. CD28 and CTLA4 share identical ligands: CD80 (also known as B7.1) and CD86 (alsoknown as B7.2)16–20. Although the exact mechanismsof CTLA4 action are under considerable debate, becauseCTLA4 has a much higher overall affinity for bothligands, it has been proposed that its expression on thesurface of T cells dampens the activation of T cells byoutcompeting CD28 in binding CD80 and CD86, as wellas actively delivering inhibitory signals to the T cell21–26.The specific signalling pathways by which CTLA4 blocksT cell activation are still under investigation, although anumber of studies suggest that activation of the proteinphosphatases, SHP2 (also known as PTPN11) and PP2A,are important in counteracting kinase signals that areinduced by TCR and CD28 (REF. 15). However, CTLA4also confers ‘signalling-independent’ T cell inhibitionthrough the sequestration of CD80 and CD86 fromCD28 engagement, as well as active removal of CD80and CD86 from the antigen-presenting cell (APC) surface27. The central role of CTLA4 for keeping T cellactivation in check is dramatically demonstrated by thelethal systemic immune hyperactivation phenotype ofCtla4‑knockout mice28,29.Even though CTLA4 is expressed by activated CD8 effector T cells, the major physiological role of CTLA4seems to be through distinct effects on the two majorsubsets of CD4 T cells: downmodulation of helperT cell activity and enhancement of regulatory T (TReg)cell immunosuppressive activity 14,30,31 (BOX 1). CTLA4blockade results in a broad enhancement of immuneresponses that are dependent on helper T cells and,conversely, CTLA4 engagement on TReg cells enhancestheir suppressive function. CTLA4 is a target gene ofthe forkhead transcription factor FOXP3 (REFS 32,33),NATURE REVIEWS CANCERVOLUME 12 APRIL 2012 253 2012 Macmillan Publishers Limited. All rights reserved
REVIEWSAntigen-presenting cellT cellPDL1 or PDL2? PDL1 or PDL2PD1–CD80 or CD86CD28 CD80 or CD86CTLA4–B7RP1ICOS B7-H3?–B7-H4?–HVEMBTLA–KIR–Peptide Signal 1TCRMHC class I or IILAG3–CD137LCD137 OX40LOX40 CD70CD27 �, IL-1,IL-6, IL-10,IL-12, IL-18)Nature Reviews CancerCD4 helper T cellsT cells that are characterizedby the expression of CD4. Theyrecognize antigenic peptidespresented by MHC class IImolecules. This type of T cellproduces a vast range ofcytokines that mediateinflammatory and effectorimmune responses. They alsofacilitate the activation of CD8 T cells and B cells for antibodyproduction.the expression of which determines the TReg cell lineage34,35, and TReg cells therefore express CTLA4 constitutively. Although the mechanism by which CTLA4enhances the immunosuppressive function of TRegcells is not known, TReg cell-specific CTLA4 knockoutor blockade significantly inhibits their ability to regulate both autoimmunity and antitumour immunity 30,31.Thus, in considering the mechanism of action forCTLA4 blockade, both enhancement of effector CD4 T cell activity and inhibition of TReg cell-dependentimmunosuppression are probably important factors.Clinical application of CTLA4‑blocking antibodies —the long road from mice to FDA approval. Initially,the general strategy of blocking CTLA4 was questioned because there is no tumour specificity to theFigure 1 Multiple co-stimulatory and inhibitoryinteractions regulate T cell responses. Depicted arevarious ligand–receptor interactions between T cells andantigen-presenting cells (APCs) that regulate the T cellresponse to antigen (which is mediated by peptide–major histocompatibility complex (MHC) moleculecomplexes that are recognized by the T cell receptor(TCR)). These responses can occur at the initiation ofT cell responses in lymph nodes (where the major APCsare dendritic cells) or in peripheral tissues or tumours(where effector responses are regulated). In general,T cells do not respond to these ligand–receptorinteractions unless they first recognize their cognateantigen through the TCR. Many of the ligands bind tomultiple receptors, some of which deliver co-stimulatorysignals and others deliver inhibitory signals. In general,pairs of co-stimulatory–inhibitory receptors that bind thesame ligand or ligands — such as CD28 and cytotoxicT‑lymphocyte-associated antigen 4 (CTLA4) — displaydistinct kinetics of expression with the co-stimulatoryreceptor expressed on naive and resting T cells, but theinhibitory receptor is commonly upregulated after T cellactivation. One important family of membrane-boundligands that bind both co-stimulatory and inhibitoryreceptors is the B7 family. All of the B7 family membersand their known ligands belong to the immunoglobulinsuperfamily. Many of the receptors for more recentlyidentified B7 family members have not yet been identified.Tumour necrosis factor (TNF) family members that bindto cognate TNF receptor family molecules represent asecond family of regulatory ligand–receptor pairs. Thesereceptors predominantly deliver co-stimulatory signalswhen engaged by their cognate ligands. Another majorcategory of signals that regulate the activation of T cellscomes from soluble cytokines in the microenvironment. Communication between T cells and APCs isbidirectional. In some cases, this occurs when ligandsthemselves signal to the APC. In other cases, activatedT cells upregulate ligands, such as CD40L, that engagecognate receptors on APCs. A2aR, adenosine A2areceptor; B7RP1, B7‑related protein 1; BTLA, B and Tlymphocyte attenuator; GAL9, galectin 9; HVEM,herpesvirus entry mediator; ICOS, inducible T cellco-stimulator; IL, interleukin; KIR, killer cell immunoglobulinlike receptor; LAG3, lymphocyte activation gene 3;PD1, programmed cell death protein 1; PDL, PD1 ligand;TGFβ, transforming growth factor‑β; TIM3, T cellmembrane protein 3.expression of the CTLA4 ligands (other than for somemyeloid and lymphoid tumours) and because the dramatic lethal autoimmune and hyperimmune phenotype of Ctla4‑knockout mice predicted a high degree ofimmune toxicity associated with blockade of this receptor. However, Allison and colleagues36 used preclinicalmodels to demonstrate that a therapeutic window wasindeed achieved when CTLA4 was partially blocked withantibodies. The initial studies demonstrated significantantitumour responses without overt immune toxicitieswhen mice bearing partially immunogenic tumours weretreated with CTLA4 antibodies as single agents. Poorlyimmunogenic tumours did not respond to anti‑CTLA4 asa single agent but did respond when anti‑CTLA4 wascombined with a granulocyte–macrophage colonystimulating factor (GM-CSF)-transduced cellular254 APRIL 2012 VOLUME 12www.nature.com/reviews/cancer 2012 Macmillan Publishers Limited. All rights reserved
F O C U S O N t u m our i m m uno lo g y & i m m unotRhpyE erV I EaWSTable 1 The clinical development of agents that target immune-checkpoint pathwaysMyeloid cellsAny white blood cell(leukocyte) that is not alymphocyte: macrophages,dendritic cells and granulocyticcells.Suicide substratesMolecules that inhibit anenzyme by mimicking itssubstrate and covalentlybinding to the active site.Antigen-presenting cell(APC). Any cell that displays onits surface an MHC moleculewith a bound peptide antigenthat a T cell recognizes throughits TCR. This can be a dendriticcell or a macrophage, or anycell that expresses antigen andwould be killed by an activatedCD8 effector T cell-specificresponse (such as a tumour cellor virally infected cell).Regulatory T (TReg) cellA type of CD4 T cell thatinhibits, rather than promotes,immune responses. They arecharacterized by theexpression of the forkheadtranscription factor FOXP3, thelack of expression of effectorcytokines such as IFNγ and theproduction of inhibitorycytokines such as TGFβ, IL‑10and IL‑35.Immunogenic tumoursIn the case of tumours in mice,this refers to a tumour thatnaturally elicits an immuneresponse when growing in amouse. With regard to humantumours, melanoma is typicallyconsidered immunogenicbecause patients withmelanoma often have increasednumbers of T cells that arespecific for melanoma antigens.Objective clinical responsesA diminution of totalcross-sectional area of allmetastatic tumours — asmeasured by a CT or MRI scan— by 30% (corresponding to 50% decrease in volume)with no growth of anymetastatic tumours.Response rateThe proportion of treatedpatients that achieve anobjective response.TargetBiological functionAntibody or Ig fusion proteinState of clinical development*CTLA4Inhibitory receptorIpilimumabFDA approved for melanoma, Phase II andPhase III trials ongoing for multiple cancersTremelimumabPreviously tested in a Phase III trial of patientswith melanoma; not currently activeMDX‑1106 (also known asBMS‑936558)Phase I/II trials in patients with melanoma andrenal and lung cancersMK3475Phase I trial in multiple cancersPD1Inhibitory receptorCT‑011‡Phase I trial in multiple cancersAMP‑224Phase I trial in multiple cancersMDX‑1105Phase I trial in multiple cancersMultiple mAbsPhase I trials planned for 2012IMP321 Phase III trial in breast cancerMultiple mAbsPreclinical developmentMGA271Phase I trial in multiple cancers§PDL1Ligand for PD1LAG3Inhibitory receptorB7‑H3Inhibitory ligandB7‑H4Inhibitory ligandPreclinical developmentTIM3Inhibitory receptorPreclinical developmentCTLA4, cytotoxic T‑lymphocyte-associated antigen 4; FDA, US Food and Drug Administration; Ig, immunoglobulin; LAG3, lymphocyteactivation gene 3; mAbs, monoclonal antibodies; PD1, programmed cell death protein 1; PDL, PD1 ligand; TIM3, T cell membrane protein 3.*As of January 2012. ‡PD1 specificity not validated in any published material. §PDL2–Ig fusion protein. LAG3–Ig fusion protein.vaccine37. These findings suggested that, if there is anendogenous antitumour immune response in the animals after tumour implantation, CTLA4 blockade couldenhance that endogenous response, which ultimately caninduce tumour regression. In the case of poorly immunogenic tumours, which do not induce substantial endogenous immune responses, the combination of a vaccine anda CTLA4 antibody could induce a strong enough immuneresponse to slow tumour growth and in some caseseliminate established tumours.These preclinical findings encouraged the production and testing of two fully humanized CTLA4 antibodies, ipilimumab and tremelimumab, which beganclinical testing in 2000. As with virtually all anticanceragents, initial testing was as a single agent in patientswith advanced disease that were not responding to conventional therapy 38. Both antibodies produced objectiveclinical responses in 10% of patients with melanoma,but immune-related toxicities involving various tissuesites were also observed in 25–30% of patients, with colitis being a particularly common event 39–41 (FIG. 2). Thefirst randomized Phase III clinical trial to be completedwas for tremelimumab in patients with advanced melanoma. In this trial, 15 mg per kg tremelimumab was givenevery three months as a single agent and compared withdacarbazine (also known as DTIC), a standard melanoma chemotherapy treatment. The trial showed nosurvival benefit with this dose and schedule relative todacarbazine42.However, ipilimumab fared better. Even though theintrinsic activity, response rates in Phase II trials andimmune toxicity profiles were similar for both antibodies, ipilimumab was more carefully evaluated at differentdoses and schedules. Additionally, more careful definitionof algorithms for improved clinical management of theimmune toxicities (using steroids and tumour necrosisfactor (TNF) blockers) mitigated the overall morbidityand mortality that were associated with immunologicaltoxicities. Interestingly, although there is evidence thatclinical responses might be associated with immunerelated adverse events, this correlation is modest43. Finally,in a randomized three-arm clinical trial of patients withadvanced melanoma that received either: a peptidevaccine of melanoma-specific gp100 (also known asPMEL) alone; the gp100 vaccine plus ipilimumab; or ipilimumab alone, there was a 3.5 month survival benefit forpatients in both groups receiving ipilimumab (that is, withor without the gp100 peptide vaccine) comparedwith the group receiving the gp100 peptide vaccinealone44. As ipilimumab was the first therapy to demonstrate a survival benefit for patients with metastaticmelanoma, it was approved by the US Food and DrugAdministration (FDA) for the treatment of advancedmelanoma in 2010 (dacarbazine was approved on thebasis of response rate but has not been shown to providea survival benefit in patients with melanoma).More impressive than the mean survival benefit wasthe effect of ipilimumab on long-term survival: 18%of the ipilimumab-treated patients survived beyond twoyears (compared with 5% of patients receiving the gp100peptide vaccine alone)44. In this and other studies, theproportion of long-term survivors was higher thanthe proportion of objective responders. The finding ofongoing responses and survival long after completionof a relatively short course of therapy (four doses of10 mg per kg over 3 months) support the concept thatimmune-based therapies might re-educate the immunesystem to keep tumours in check after completion of thetherapeutic intervention.As with all oncology agents that benefit a limited proportion of treated patients, there has been much effortin defining biomarkers that predict clinical responsesNATURE REVIEWS CANCERVOLUME 12 APRIL 2012 255 2012 Macmillan Publishers Limited. All rights reserved
REVIEWSNatural killer (NK) cellsImmune cells that kill cellsusing mechanisms similar toCD8 effector T cells but donot use a clonal TCR forrecognition. Instead, they areactivated by receptors forstress proteins and areinhibited through distinctreceptors, many of whichrecognize MHC moleculesindependently of the boundpeptide.AnergyA form of T or B cellinactivation in which the cellremains alive but cannot beactivated to execute animmune response. Anergy is areversible state.to anti‑CTLA4 therapy. To date, no such pretreatmentbiomarker has been validated to the point at which itcould be applied as part of standard-of-care therapeutic decision-making, although insights have emergedfrom the identification of certain post-treatmentimmune responses that seem to correlate with clinicaloutcome45–47.An important feature of the anti‑CTLA4 clinicalresponses that distinguishes them from conventionalchemotherapeutic agents and oncogene-targeted smallmolecule drugs is their kinetics. Although responses tochemotherapies and tyrosine kinase inhibitors (TKIs)commonly occur within weeks of initial administration,the response to immune-checkpoint blockers is slowerand, in many patients, delayed (up to 6 months aftertreatment initiation). In some cases, metastatic lesionsactually increase in size on computed tomography (CT)or magnetic resonance imaging (MRI) scans beforeregressing, which seems to occur owing to increasedimmune cell infiltration. These findings demand a reevaluation of response criteria for immunotherapeutics away from the conventional time-to-progressionor Response Evaluation Criteria in Solid Tumours(RECIST) objective response criteria, which were developed on the basis of experiences with chemotherapeuticagents and as the primary measure of drug efficacy 48.Blockade of the PD1 pathwayAnother immune-checkpoint receptor, PD1, is emerging as a promising target, thus emphasizing the diversityof potential molecularly defined immune manipulations that are capable of inducing antitumour immuneresponses by the patient’s own immune system.The biology of the PD1 pathway. In contrast to CTLA4,the major role of PD1 is to limit the activity of T cellsin peripheral tissues at the time of an inflammatoryBox 1 TReg cells in the maintenance of immune tolerance in cancerRegulatory T (TReg) cells are crucial for the maintenance of self-tolerance. Their uniquegenetic programme is driven by the forkhead transcription factor FOXP3, which isencoded on the X chromosome. Foxp3‑knockout mice, and humans with homozygousmutation of FOXP3 (which causes immunodysregulation, polyendocrinopathy,enteropathy and X‑linked (IPEX) syndrome) develop autoimmune syndromes involvingmultiple organs30–33. The inhibitory activity of TReg cells on immune responses remains tobe completely understood, but involves the production of inhibitory cytokines, such astransforming growth factor‑β (TGFβ), interleukin‑10 (IL‑10) and IL‑35. They aresubdivided into ‘natural’ TReg (nTReg) cells, which develop in the thymus, and ‘induced’TReg (iTReg) cells, which accumulate in many tumours and are thought to represent amajor immune resistance mechanism. They are therefore viewed as important cellulartargets for therapy. TReg cells do not express cell surface molecules that are unique toeither subset, but they do express high levels of multiple immune-checkpoint receptors,such as cytotoxic T‑lymphocyte-associated antigen 4 (CTLA4), programmed cell deathprotein 1 (PD1), T cell membrane protein 3 (TIM3), adenosine A2a receptor (A2aR) andlymphocyte activation gene 3 (LAG3). Genes encoding some of these immunecheckpoint receptors, such as CTLA4, are actually FOXP3 target genes. Paradoxically,although inhibiting effector T cells, these receptors seem to enhance TReg cell activity orproliferation. Although an antibody that specifically targets TReg cells has not yet beenproduced, many of the immune-checkpoint antibodies in clinical testing probably blockthe immunosuppressive activity of TReg cells as a mechanism of enhancing antitumourimmunity.response to infection and to limit autoimmunity49–55(FIG. 3). This translates into a major immune resistancemechanism within the tumour microenvironment56–58.PD1 expression is induced when T cells become activated49. When engaged by one of its ligands, PD1 inhibits kinases that are involved in T cell activation throughthe phosphatase SHP250, although additional signallingpathways are also probably induced. Also, because PD1engagement inhibits the TCR ‘stop signal’, this pathwaycould modify the duration of T cell–APC or T cell–target cell contact59. Similarly to CTLA4, PD1 is highlyexpressed on TReg cells, where it may enhance theirproliferation in the presence of ligand60. Because manytumours are highly infiltrated with TReg cells that probably further suppress effector immune responses, blockade of the PD1 pathway may also enhance antitumourimmune responses by diminishing the number and/orsuppressive activity of intratumoral TReg cells.The two ligands for PD1 are PD1 ligand 1 (PDL1; alsoknown as B7‑H1 and CD274) and PDL2 (also knownas B7‑DC and CD273)50,61–63. These B7 family membersshare 37% sequence homology and arose through geneduplication, which has positioned them within 100 kbof each other in the genome63. Recently, an unexpectedmolecular interaction between PDL1 and CD80 was discovered64, whereby CD80 expressed on T cells (and possibly APCs) can potentially behave as a receptor ratherthan a ligand by delivering inhibitory signals whenengaged by PDL1 (REFS 65,66). The relevance of this interaction in tumour immune resistance has not yet beendetermined. Finally, genetic evidence from PD1‑deficientT cells suggests that both PDL1 and PDL2 may bind toa co-stimulatory receptor that is expressed on T cells67.These complex binding interactions are reminiscentof the CD80 and CD86 ligand pair, each of which bindsthe co-stimulatory receptor CD28 that is expressed onresting T cells and the inhibitory receptor CTLA4 that isexpressed on activated T cells. However, as stated above,PD1 predominantly regulates effe
in cancer immunotherapy Drew M. Pardoll Abstract Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints re
May 02, 2018 · D. Program Evaluation ͟The organization has provided a description of the framework for how each program will be evaluated. The framework should include all the elements below: ͟The evaluation methods are cost-effective for the organization ͟Quantitative and qualitative data is being collected (at Basics tier, data collection must have begun)
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Chính Văn.- Còn đức Thế tôn thì tuệ giác cực kỳ trong sạch 8: hiện hành bất nhị 9, đạt đến vô tướng 10, đứng vào chỗ đứng của các đức Thế tôn 11, thể hiện tính bình đẳng của các Ngài, đến chỗ không còn chướng ngại 12, giáo pháp không thể khuynh đảo, tâm thức không bị cản trở, cái được
Le genou de Lucy. Odile Jacob. 1999. Coppens Y. Pré-textes. L’homme préhistorique en morceaux. Eds Odile Jacob. 2011. Costentin J., Delaveau P. Café, thé, chocolat, les bons effets sur le cerveau et pour le corps. Editions Odile Jacob. 2010. Crawford M., Marsh D. The driving force : food in human evolution and the future.
ELSEVIER Artificial Intelligence 82 ( 1996) 369-380 Book Review Stuart Russell and Peter Norvig, Artificial Intelligence Artijcial Intelligence: A Modem Approach * Nils J. Nilsson Robotics Laboratory, Department of Computer Science, Stanford University, Stanford, CA 94305, USA 1. Introductory remarks I am obliged to begin this review by confessing a conflict of interest: I founding director .
