医学免疫学课件：Regulatory T lymphocytes in Cancer Mechanisms and Treatments

1、Regulatory T lymphocytes in Cancer: Mechanisms and TreatmentsFrameworkTreg introductionsTypesCorrelationsIn cancer treatmentsClinical impactsBiomarkers as targetsIn cancer progressions and invationsMechanisms1Tregs-IntroductionsImmune homeostasisEliminate foreign antigens: Effector T cellsSelf recog

2、nition and tolerance: Regulatory T cellsInflammation and autoimmune inhibitionET/RT ratio2Treg in TumorRegulatory T cellsPlasticity: Signals recruitmentInflammation sites/ TME traffickingIntervention, expansion, overexpressionParacrine and autocrineTregs in Tumors Microenvironment enrichmentTumor su

3、ppression and eliminationCancer developmentimmune escape (manipulation)3Chaudhary B, Samid M A, Alramadi B K, et al. Phenotypic alterations, clinical impact and therapeutic potential of regulatory T cells in cancerJ. Expert Opinion on Biological Therapy, 2014, 14(7): 931-945.4Treg typestTreg: Thymus

4、- derivedmaintenance of peripheral tolerancelimit autoimmunity and tissue pathology pTreg: Peripheral-derivedlimit local immune pathologies at environmental boundaries Tumor microenvironment(TME)RecruitmentDiscrimination good or bad5Markers and TargetsMarkersSurface markers Intracellular markersChem

5、okine receptorsChemokine blockadeTargetsCombinationsImmune checkpoint blockadeImmune agonistsTumor specific vaccinesRadiotherapychemotherapy6Chaudhary B, Samid M A, Alramadi B K, et al. Phenotypic alterations, clinical impact and therapeutic potential of regulatory T cells in cancerJ. Expert Opinion

6、 on Biological Therapy, 2014, 14(7): 931-945.7Mice Models to Clinical Trials Inadequate depletionInnate resistenceSelective sensitivityTreg repopulation89Chaudhary B, Samid M A, Alramadi B K, et al. Phenotypic alterations, clinical impact and therapeutic potential of regulatory T cells in cancerJ. E

7、xpert Opinion on Biological Therapy, 2014, 14(7): 931-945.StrategiesBreak down tumor toleranceBlocking Treg cell functions10Metabolic SignaturesActivated CD4+ T cells Teff cell lineage (TH1 or TH17 cells) glucose and glutamine anabolic metabolism. pTreg cells iTreg cell lineage in vitro exogenous li

8、pids, glucose-derived pyruvate TCA cycletTreg cells resemble activated Teff cellsglucose and glutamine1112Newton R, Priyadharshini B, Turka L A. Immunometabolism of regulatory T cellsJ. Nature Immunology, 2016, 17(6):618-625FoxP3 and Treg GenerationFoxp3 expressionNAD+ and NADH Signaling molecules f

9、rom glycolysis and mitochondriaActivation PI(3)K-Akt-mTOR signaling pathwayT-cell stabilityEZH2 inhibited by specific microRNAsglucose deprivationETC, electron-transport chain; PRC, polycomb repressive complex; IP3 and IP3R, inositol-1,3,4-trisphosphate1314Newton R, Priyadharshini B, Turka L A. Immu

10、nometabolism of regulatory T cellsJ. Nature Immunology, 2016, 17(6):618-625LimitationsTumor typeInflammatory / tumor escapeTumor effectsOutcome and PrognosisRecurrenceComplicationsautoimmune diseases, organ transplantationTreg type specific targetstTreg pTreg iTregDrug dosesDepletion and duration15R

11、eferencesWhiteside T L. The role of regulatory T cells in cancer immunologyJ. Journal of Molecular Biology, 2015, 58(1):329-348.Liu C, Workman C J, Vignali D A A. Targeting Regulatory T Cells in TumorsJ. Febs Journal, 2016.Wolf D, Sopper S, Pircher A, et al. Treg(s) in Cancer: Friends or Foe?J. Jour

12、nal of Cellular Physiology, 2015, 230(11):2598-605.Takeuchi Y, Nishikawa H. Roles of regulatory T cells in cancer immunityJ. International Immunology, 2016, 28(8):dxw025.Chaudhary B, Abd A S M, Al-Ramadi B K, et al. Phenotypic alterations, clinical impact and therapeutic potential of regulatory T ce

13、lls in cancer.J. Expert Opinion on Biological Therapy, 2014, 14(7):931-45.Newton R, Priyadharshini B, Turka L A. Immunometabolism of regulatory T cellsJ. Nature Immunology, 2016, 17(6):618-625.Perdigoto A L, Chatenoud L, Bluestone J A, et al. Inducing and Administering Tregs to Treat Human Disease.J. Frontiers in Immunology, 2016, 6(6).1