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Barbara Seliger

T ERASAKI FESTSCHRIFT January 24-26, 2014 Los Angeles, CA HLA-G and HLA-E in tumors. Barbara Seliger. Institute of Medical Immunology – Martin Luther University Halle-Wittenberg Halle, Germany. Barbara Seliger. Immune escape strategies of tumors. tumor cells. micromilieu.

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Barbara Seliger

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  1. TERASAKI FESTSCHRIFT January 24-26, 2014 Los Angeles, CA HLA-G and HLA-E in tumors Barbara Seliger Institute of Medical Immunology – Martin Luther University Halle-Wittenberg Halle, Germany

  2. Barbara Seliger

  3. Immune escapestrategiesoftumors tumor cells micromilieu immune cells MHC HLA-G/-E B7-H1/4 altered signaling pH metabolites suppressive cytokines hypoxia CD8+ T, DC and NK function Treg MDSC

  4. Immune escapestrategiesoftumors tumor cells micromilieu immune cells MHC HLA-G/-E B7-H1/4 altered signaling pH metabolites suppressive cytokines hypoxia CD8+ T, DC and NK function Treg MDSC

  5. HLA-G and HLA-E: non-classical HLA class Ib antigens • uniquefeaturescomparedtoclassical HLA class I • lowpolymorphism • restrictedand/ortightlycontrolledexpression • interactionwithreceptors on NK and T cells • inhibition of NK and CD8+ T cell-mediatedcytotoxicity • pathophysiologicexpression on solid andhematopoetictumors of distinctorigin

  6. High frequency of HLA-G mRNA and protein expression in tumors of different origin frequent discordant mRNA and protein expression involvement of microRNAs? altered Seliger et al., 2011

  7. Clinical relevance of HLA-G expression in human tumors • associationofmembraneousand soluble HLA-G • expression in tumorswithtumorgradingand • staging • enhanceddiseaseprogressionof HLA-G+ tumors • correlationof HLA-G expressionwithreduced • survivalofpatients • HLA-G asprognosticordisagnosticmarker?

  8. Molecular mechanisms of aberrant HLA-G expression HLA-G structural alterations deletions/mutations polymorphisms

  9. Molecular mechanisms of aberrant HLA-G expression HLA-G structuralalterationsdeletions/mutations polymorphisms deregulation post-transcription transcription epigenetics

  10. Molecular mechanisms of aberrant HLA-G expression HLA-G structuralalterationsdeletions/mutations polymorphisms deregulation post-transcription (miR) transcription epigenetics

  11. In silico analysis, miR arrays and mi-TRAP: identification of HLA-G regulatory miRs key regulators fine tuners marginal enrichment

  12. Functional activity of miR-152 and miR-628 in JEG-3 cells: downregulation of HLA-G pmR(miR-541) pmR(miR-628) pmR(miR-152) pmR(mock) HLA-G GAPDH MEM-G/4 purchased from Exbio, Praque • correlationof HLA-G-specificmiRexpressionwith • altered immune recognition, • enhanced NK and LAK cellmediatedcytotoxicity

  13. Role of HLA-G-specific miRs • immunohistochemicalanalysisof a tumor-specifictissuemicroarray (HLA-G/miR) • comparisonoftheexpressionpatternof HLA-G andmiRs • associationof HLA-G-specificmiRexpressionwithclinicalparameters

  14. Inverse correlation between HLA-G and miR-148 expression in RCC tumor lesions n = 36 n = 36 n = 36 n = 36 • association with tumor grading and staging

  15. Identification of novel targets for the HLA-G-specific miR-148 dual role of miR-148 and HLA-G immuno- growth genicity properties miR-148 synergistic effects malignant phenotype

  16. What about HLA-E? • higher HLA-E expressionlevels in solid and • hematopoietictumors (e.g. melanoma, colon • carcinoma, breastcancer, cervicalcancer, • glioblastoma, lymphoma…) • associatedwithpoorpatients` outcome • controversialresults due to HLA-E mAbs • avaílable

  17. Barbara Seliger

  18. Different expression profile of HLA-E expression in normal tissues placenta: HLA-E - lymph node: HLA-E - renal tubules: HLA-E + + + lung: HLA-E + in alveolar macrophages mamma: HLA-E + + salivary gland: HLA-E + + + mAb: TFL-033 collaboration with Prof. A. Hartmann, Inst. of Pathology, Erlangen Prof. Paul Terasaki, Dr. M. Ravindranath, TFL, LA

  19. Heterogeneous expression of HLA-G and HLA-Ein renal cell carcinoma ranging from negative to strong positive HLA-G - HLA-G + HLA-G + + + HLA-E + + HLA-E + + + HLA-E + mAb: TFL-033 collaboration with Prof. A. Hartmann, Inst. of Pathology, Erlangen Prof. P. Terasaki, Dr. M. Ravindranath, LA

  20. Association of tumor infiltrating lymphocytes with HLA-G and -E expression in RCC lesions CD8 staining at HLA-G- RCC CD8 staining at HLA-G+ RCC • no correlation of immune infiltration with HLA-E collaboration with A. Hartmann, Erlangen P. Terasaki, M. Ravindranath, LA

  21. No link between the expression of miR-148A/152 and HLA-E in RCC tumor lesions absolute copy number miR-152 absolute copy number miR-148A n = 36 n = 36 n = 36 n = 36 • other miRs responsible

  22. Mode of HLA-G-/-E regulation and function immune recognition tumor suppressor apoptosis miR expression expression of growth/ apoptosis related genes/proteins HLA-G/-E expression proliferation immune escape tumorigenic increased tumor grading & staging decreased overall survival

  23. Barbara Seliger

  24. The future of HLA-G and -E in tumors…. • useofmembraneousand/or soluble HLA-G • and -E expressionasdiagnosticand/or • prognostictoolsfortumors • implementationof HLA-G- and -E-specific • antibodiesfortherapyto block sHLA-G/-E • developmentandestablishmentof HLA-G- • and -E-specificmiRsforthetreatmentof • tumorpatients

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