1 / 25

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.

herne
Download Presentation

Barbara Seliger

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related