MP24-17 INTERLEUKIN-15 DOWNREGULATES INHIBITORY NATURAL KILLER(NK) CELL LIGANDS EXPRESSED ON PROSTATE CANCER CELLS RESULTING IN INCREASED NK CELL ACTIVITY IN PROSTATE CANCER-IMMUNE EFFECTOR CELL COCULTURES.

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2014MP24-17 INTERLEUKIN-15 DOWNREGULATES INHIBITORY NATURAL KILLER(NK) CELL LIGANDS EXPRESSED ON PROSTATE CANCER CELLS RESULTING IN INCREASED NK CELL ACTIVITY IN PROSTATE CANCER-IMMUNE EFFECTOR CELL COCULTURES. Christine Galustian, Christina Sakellariou, Oussama Elhage, Osamu Ukimura, Inderbir Gill, Richard Smith, and Prokar Dasgupta Christine GalustianChristine Galustian More articles by this author , Christina SakellariouChristina Sakellariou More articles by this author , Oussama ElhageOussama Elhage More articles by this author , Osamu UkimuraOsamu Ukimura More articles by this author , Inderbir GillInderbir Gill More articles by this author , Richard SmithRichard Smith More articles by this author , and Prokar DasguptaProkar Dasgupta More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.298AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The prostate cancer microenvironment is profoundly immunosuppressive and NK cells and T cells that infiltrate this environment are rendered anergic or suppressive. Recently, immunomodulatory checkpoints such as PDL1 and CTLA-4 have been shown to be important in creating this immunosuppression. Antibodies to these have a moderate effect in suppressing tumour growth but many unknown immunosuppressive factors exist on tumour cells. We have shown that prostate cancer cells express a wide range of ligands that inhibit NK cell activity by binding to inhibitory Killer Ig like receptors (KIRs). These receptors are critical in modulating the function of NK cells. Also, these cells have a downregulated expression of HLA molecules that render them less susceptible to T cell mediated recognition and killing. We have shown that IL-15, unlike other immunotherapeutic cytokines (e.g IL-12, IL-21), increases NK and CD8-T-cell activity within the prostate cancer microenvironment. We have previously demonstrated that IL-15 upregulates activatory KIRs and downregulates inhibitory KIRs to increase NK cell activity. To further these investigations, we have now examined the effects of IL-15 on ligands on prostate cancer cells that are recognised by activatory and inhibitory KIRs. METHODS PC3 and LNCaP prostate cancer cell-lines were incubated with non-adherent PBMCs at effector:target ratios of 8:1 and cytokines IL-2 or IL-15. After 1 week, Tumour cells were stained with antibodies to inhibitory HLA-class1-BW4 and HLA-G, and activatory Nectin-2 and MICA/MICB KIR-ligands. Antibody to HLA-ABC was also used. Flow cytometric analysis followed staining. RESULTS IL-15, but not IL-2 decreased the inhibitory-ligands HLA-Class-1-BW4 by upto 60%* on both LNCaP and PC3 cells. IL-15 also decreased the expression of HLA-G by 75%* on LNCaP cells. HLA-A,B,C expression was increased by over 65%* in the two prostate cancer cell lines. Initial data showed that activatory-ligands were not affected on either PC3 or LNCaP tumour cells. * =(p<0.001,1-way-anova, post-hoc Newman-Keuls,n=5). CONCLUSIONS IL-15 can downregulate inhibitory NK ligands on prostate cancer cells in addition to its ability to modulate activatory and inhibitory KIRs. This suggests strong shifts toward NK activation vs inhibition in the cocultures. Increased HLA-A,B,C on the tumour cells also favours stronger cytotoxic-T cell recognition. The molecular basis of these effects are currently being investigated. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e265 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Christine Galustian More articles by this author Christina Sakellariou More articles by this author Oussama Elhage More articles by this author Osamu Ukimura More articles by this author Inderbir Gill More articles by this author Richard Smith More articles by this author Prokar Dasgupta More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...