医学免疫学课件：NK Cells and Tumor

1、NK Cells and Tumor1.Introduction to NK cells 1.1Development 1.2subsets 1.3Receptor and recognition 2NK cells attack tumor cell 2.1Releasing perforin and granzymes 2.2Fas-L and TRAIL mediated apoptosis 2.3antibody-dependent cellular cytotoxicity (ADCC) 2.4producing cytokines3 the role of NK cells in

2、tumor immunity4 challengeIntroductionNatural killer sellno MHCrestrictionAntibody-independentWithout prior sensitization Effect cell in adaptive immune systemconstitute 515% of peripheral blood lymphocytesSubsetDefined by CD56+, CD16+, CD3-According to the density of CD56 SubsetCD56dim: high cytotox

3、ic potential in blood (90%95%) or at inflammation sites CD56bright: little cytotoxicity mainly produce immunoregulatory cytokines lymph nodesReceptoractivating receptorsinhibitory receptorsinhibitedactive?ReceptorFcRIIIKIR2DS and KIR3DSNKG2DNCRs:NKp30,NKp44,NKp46CD94/NKG2C,NKG2E/H NKG2FKIR2DL,KIR3DL

4、ILT2NKG2AActivating receptorInhibitory receptorimmunoreceptor tyrosine-based inhibitory motifs(ITIM) Figure 1. Innate immune recognition by NK cells. The figure illustrates three different modes of innate immune recognition, as mediated by NK cells in this example. (a) Direct recognition of microbia

5、l nonself. MCMV-infected target cell expresses the viral pr.Andreas Diefenbach, David H Raulet Innate immune recognition by stimulatory immunoreceptorsCurrent Opinion in Immunology, Volume 15, Issue 1, 2003, 3744 Non-selfMissing-selfInduced-selfNK cell recognize tumor cellTumor cells decrease expres

6、sion of MHC-I in order to evade cytotoxic T lymphocyte (CTL) detection up-regulate activating ligands under stressFunctions targeting tumor cells Releasing perforin and granzymes Fas-L and TRAIL mediated apoptosis antibody-dependent cellular cytotoxicity (ADCC) producing cytokinesPerforin and granzy

7、mesPerforin a pore forming cytolytic protein found in the granules of Cytotoxic T lymphocytes (CTLs) and NK cellsproduces pores of up to 20 nm in diameter on target membranes and allows granzymes in to the target cell.Granzymes serine proteases that are released by cytoplasmic granules within cytoto

8、xic T cells and natural killer (NK) cells. induce programmed cell death in the target cellReleasing perforin and granzymesIn immunology, an immunological synapse (or immune synapse) is the interface between an antigen-presenting cell or target cell and a lymphocyte such as an effector T cell or Natu

9、ral Killer cell.Immune synapsesupramolecular activation cluster(SMAC)pSMACcSMAC Figure 1. The NK cell immunological synapse is formed in distinct stages. The encounter between the NK and a target cell results in adhesion and conjugate formation (top). The balance between activating and inhibitory re

10、ceptor signaling on the cellcell interf.Konrad Krzewski, Jack L Strominger The killers kiss: the many functions of NK cell immunological synapsesCurrent Opinion in Cell Biology, Volume 20, Issue 5, 2008, 597605 Death receptor mediated apoptosisDeath receptor on tumor cellsFas and DR5Members of tumor

11、 necrosis factor (TNF) familyLigand: FasFasL DR5TNF-related apoptosis-inducing ligand (TRAIL) ADCC The antibody-dependent cell-mediated cytotoxicity (ADCC) is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose membrane-surfac

12、e antigens have been bound by specific antibodies.ADCCIgGRely on granzyme releasingPlay an important role in cancer therapy using Monoclonal antibody Producing cytokinesProducing IFN-, TNF-, TGF-, interleukin (IL)-10, or IL-13 granulocyte-macrophage colony-stimulating factor (GM-CSF)IFN-eliminate tu

13、mor metastases and sarcoma induced by methylcholanthrene in a murine modelinhibits proliferation of tumor cells in vitro and indirectly the tumor growth in vivo by inducing the antiangiogenic factors, IP-10. enhance NK cell cytotoxicity by overexpressing adhesion molecules or by increasing the sensi

14、tivity of tumor cells induced TRAIL expression NK cells in tumor immunityNK cells can recognize and attack cancer cells quickly before B cells and T cells effectively eliminate cancer cellsIndividual with low NK cell activity have a higher incidence of cancerplay an important role in the tumor immun

15、osurveillanceNK cell-based cancer immunotherapyFeature:antigen nonspecificitywithout prior sensitizationshorter life spaneasy to isolate and expand ex vivoHarnessing endogenous NK cells Using exogenous NK cells via HSCT or ACT modelsChallengespreferentially mount responses against hematological mali

16、gnancies or cancer metastasis than solid tumorsevasion from NK-cell attack in tumor microenvironmentNK-cell suppressiontumor-cell immunoediting direct mechanism indirect mechanismTumor microenvironmentblood vesselsTumor-associated fibroblasts(TAFs)immune cellssignaling moleculesextracellular matrix

17、(ECM)releasing extracellular signals, promoting tumor angiogenesisinducing peripheral immune toleranceaffect the growth and evolution of cancerous cellsimmuno-editingIndirect mechanismTreg cellsTGF- inhibits the expression of NKp30 and NKG2Ddirectly suppress by membrane-bound TGF-compete with NK cel

18、ls for IL-2 availabilityDirect mechanism Fig. 1. Regulation of NK cell cytotoxicity during cancer immunosurveillance. NK cells interact with cancer cells through activating (in green) and inhibitory (in red) NK cell receptors with cognate activating (in green) and inhibitory (in red) ligands on targ

19、e.Jens Pahl, Adelheid Cerwenka Tricking the balance: NK cells in anti-cancer immunityImmunobiology, 2015, Available online 26 July 2015ReferencePahl J, Cerwenka A. Tricking the balance: NK cells in anti-cancer immunityJ. Immunobiology, 2015.Jacobs R, Hintzen G, Kemper A, et al. CD56bright cells differ in their KIR repertoire and cytotoxic features from CD56dim NK cellsJ. European journal of immunology, 2001, 31(10): 3121-3126.Langers I, Renoux VM, Thiry M, Delvenne P, Jacobs N. Natural killer cells: role in local tumor growth and metastasis. Biologics: Tar