The Journal of Experimental Medicine
Published November15,2004
[email protected] Victoria, Australia.Phone:61-3-9656-3728; Fax:61-3-9656-1411;email: Peter MacCallumCancerCentre, Locked Bag1,A’BeckettSt.,8006, Address correspondencetoMarkSmyth, CancerImmunologyProgram, arms ofimmunity(5),producedbyAPCandactingupon tial roleintheinteractionbetweeninnateandadaptive in micetoalargeextentviaNKcells.IL-12playsanessen- have alsobeenshowntomediatetheirantitumoractivities IL-12 (2)andIL-18(3)orcombinationIL-2/IL-18(4), promising cytokinesincancerimmunotherapy,including activate NKandTcellsthatexpressIL-2receptors.Other cacy ofIL-2iscloselyrelatedtoitsabilityexpandand metastatic tumors(1).Themechanismofantitumoreffi- is capableofmediatingthedurableregressionestablished has demonstratedthatmanipulationoftheimmunesystem in patientswithmetastaticmelanomaandrenalcellcancer tumorimmunologyandimmunotherapy.TheuseofIL-2 in Cytokines haveplayedanimportantroleinnewprogress Introduction
1325 Wayne M. Yokoyama, e od:tumor•NKcell •FasligandIL-2IL-18 Key words: related apoptosis-inducingligandandtheNKG2Dstatusoftumormetastases. made giventheknownsensitivityoftumorcellstoperforin,FasL,andnecrosisfactor– pressing perforin-mediated cytotoxicityappearedrelativelymoreeffectiveagainsttumormetastasesex- both perforinandFasLeffectormechanismswithverypotenteffects.Cytokinesthatstimulated not dependontheNKG2D–NKG2Dligandpathway.AcombinationofIL-2andIL-18stimulated toxicity. Bycontrast,IL-18requiredtumorsensitivitytoFasligand(FasL)andsurprisinglydid suppressed tumormetastaseslargelyviaNKG2Dligandrecognitionandperforin-mediatedcyto- NK cellstorecognizeandsuppresstumormetastases.Inparticular,interleukin(IL)-2orIL-12 pression ofNKG2Dligandsontumorsprovidesaneffectivetargetforsomecytokine-stimulated pathway playsinimmunotherapyhasnotbeenexploredtodate.Here,weshowthatnaturalex- membrane stimulatoryNKG2Dimmunoreceptor;however,therolethistumorrecognition spontaneous andexperimentalcancersnaturallyexpressligandsforthelectin-liketype-2trans- Single andcombinationcytokinesofferpromiseinsomepatientswithadvancedcancer.Many 4 3 2 1 and Yoshihiro Hayakawa Mark J. Smyth, Abstract Mediate Effective CytokineImmunotherapy ofCancer NKG2D Recognition andPerforin EffectorFunction Basic Research Program,Basic Research Inc., SAIC-Frederick NationalCancerInstitute, Frederick, MD21702 Skirball InstituteofBiomolecularMedicine, New York University MedicalCenter, New York, NY10016 Howard HughesMedicalInstitute, Washington ofMedicine, UniversitySchool StLouis, MO63110 Cancer Immunology Program, Trescowthick Laboratories, PeterMacCallumCancerCentre, EastMelbourne, 8006 Victoria,Australia http://www.jem.org/cgi/doi/10.1084/jem.20041522 The JournalofExperimental Medicine NKG2D ligands.Thesefindingsindicatethatarationalchoiceofcytokinescanbe 1 Jeremy Swann, 2 Andreas Diefenbach, Andreas 1 differentiation, allowingpotentproductionofIFN- IL-12 isalsothemajorcytokineresponsibleforTh1cell T cellsandNKtogeneratecytotoxiclymphocytes. mor cellshaspavedtheway forthedesignofimproved hibitory receptorsrecognizingcorrespondingligandsontu- kill targetcellsthroughacomplexsetofactivatingandin- (10, 12). erable therapeuticactivityinseveralmurinetumormodels Systemic administrationofIL-18hasdemonstratedconsid- and FasL-orperforin-mediatedantitumoractivity(9–11). tolytic activity(7,8)andtheexpressionofFasligand(FasL) T andNKcellcytokineproduction,proliferation,cy- described asanIFN- is apotentimmunoregulatorycytokinethatwasinitially Abbreviations usedinthispaper: apoptosis-inducing ligand. perforin; MIC,MHCclassIchain–related molecule;TRAIL,TNF-related 1 Janice M. Kelly, Recent understandingofthemeansbywhichNKcells •Vlm 0,Nme 0 oebr1,20 1325–1335 November15,2004 •Volume200,Number 10, 3 Thomas J. Sayers, 1 –inducing factor(6).IL-18enhances Erika Cretney, Erika asGM1,asialoGM1;FasL,Fasligand; pfp, 4
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