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2004 NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer Mark J. Smyth Peter MacCallum Cancer Centre
Jeremy Swann Peter MacCallum Cancer Centre
Janice M. Kelly Peter MacCallum Cancer Centre
Erika Cretney Peter MacCallum Cancer Centre
Wayne M. Yokoyama Washington University School of Medicine in St. Louis
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Recommended Citation Smyth, Mark J.; Swann, Jeremy; Kelly, Janice M.; Cretney, Erika; Yokoyama, Wayne M.; Diefenbach, Andreas; Sayers, Thomas J.; and Hayakawa, Yoshihiro, ,"NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer." Journal of Experimental Medicine.,. 1325-1335. (2004). https://digitalcommons.wustl.edu/open_access_pubs/613
This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Mark J. Smyth, Jeremy Swann, Janice M. Kelly, Erika Cretney, Wayne M. Yokoyama, Andreas Diefenbach, Thomas J. Sayers, and Yoshihiro Hayakawa
This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/613
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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