醫(yī)學(xué)免疫學(xué)課件：T細(xì)胞腫瘤免疫

1、Immune escape mechanism of tumor and immune checkpoint therapyHallmarks of Cancer, 20006 main characteristics of cancer cellsSustain AngiogenesisEvade apoptosisProduce own growth signalsInsensitive to anti-growth signals(p53)StrategiesVEGF InhibitorHER2- HerceptinHallmarks of Cancer: the Next Genera

2、tion, 2011Emerging hallmarksAvoid immune destructionCancer immunologyMajor concern in medical fieldCancer and microbiotaT cell exclusion, tumor microenvironmentAdoptive cell transferNeoantigensImmune checkpoint therapyPublic awarenessMelanomaCombination therapyRadiation therapyImmune checkpoint ther

3、apyIncrease public attentionWhat is immune checkpoint therapy?Tumor antigen presentationIn normal conditionno activationIn tumor- CTL activationapoptosis Product of oncogeneOverexpressed self proteinMutated self proteinImmune tolerance & anergyAPC in tissue Present MHC IINon-Self antigenPresent in M

4、HC TCR(strong)B7 in APCCD28 in Nave T cell(CD4+) Co-stimulationImmune AnergyNo co-stimulationInhibitory receptorCTLA-4PD-1 (minor)How can tumor evade immune responses?CTL-police, tumor- criminal, antigen-IDStrategies “I forget my ID, sorry” escapeNO tumor antigen in MHC-1“Oh I am not checking ID wit

5、h you!” NK cellNO MHC-1“I am controlling your mind!”Inhibitory ligandPD-L1Inhibition of T cell activationHow can Tumor cell down regulate T cells?CTLA4-B7 in TH CellsPD1/PDL1 in CTLDiscovery of PD-L1 (B7-H1)Discovery of PD-L1 (B7-H1)Mock melanoma cellsM15 activated CTL cellsPD-1/ PDL1Tumor microenvi

6、ronment- PDL-1Tumor cellsTreg cellsAPC cellsPD1CTLNK cellsMolecular shieldPD-1/PDL1Second Gate of immune tolerancePD-L1 “-/-” autoimmune diseaseFirst gate is selection in ThymusTumor “borrow” the second gateTumor is quite clever!CTLA-4TH Cells and APC cellsctla-4 expressionCompete with CD28CTLA-4-”R

7、estaurant”Tumor - Food, APC-waiter, Th cell customerCtla-4 “I AM FULL!”CD-28”I NEED MORE!”Strategy of CTLA-4 antibody- “STAY HUNGRY” Immune checkpoint therapyAnti PD-1/PDL1 block the down regulate of CTLAnti CTLA-4 Block the down regulation of T helper cellAnti-CTLA4 mAbDramatic responseFiltration o

8、f CD8 T cell in tumor tissueOverall survival CTLA-4Overall survival of anti-PD-1 mAbPD-1 vs CTLA-4squamous non-small cell lung cancer. responsePD-L1 as a potential biomarkerCombinational therapyDifferent strategyThe future of immune checkpoint therapyTumor microenvironmentWhy always melanoma?Combinational therapyThe two roads- genomically targeted & immune checkpoint therapyGenomically targeted agentsMutationSequence for new muta