1、树突状细胞与肿瘤免疫研究进展Development Myeloid DC Plasmacytoid DC#NATURE REVIEWS|IMMUNOLOGYVOLUME 12|APRIL 2012Dendritic cellsPresence of danger signalsAdaptive immunityAntigen presentationInnate immunityAbsence of danger signalsImmune toleranceDendritic cellsPresence of danger signalsAdaptive immunityAntigen pr
2、esentationInnate immunityAbsence of danger signalsImmune toleranceAntigen presentationKuby Immunology 6th editionEndogenous antigenKuby Immunology 6th editionExogenous antigen MHC II Invariant chain CLIP (Class II-associated Invariant Chain Peptide)HLADM和HLADOKuby Immunology 6th editionActivation of
3、 T cell Signal1 Signal2 CytokinesKuby Immunology 6th editionDendritic CellsNot only antigen presentation!Dendritic cellsPresence of danger signalsAdaptive immunityAntigen presentationInnate immunityAbsence of danger signalsImmune toleranceInduce innate immunityIMMUNOBIOLOGY OF DENDRITIC CELLS Jacque
4、s Banchereau et al.Annu.Rev.Immunol.2000.18:767811Dendritic cellsPresence of danger signalsAdaptive immunityAntigen presentationInnate immunityAbsence of danger signalsImmune toleranceImmune tolerance#Journal of Cancer Molecules 2(6):213-215,2006.Dendritic cellsPresence of danger signalsAdaptive imm
5、unityAntigen presentationInnate immunityAbsence of danger signalsImmune toleranceTumor microenvironment and DCsHot IssueConvert differentDCs to macrophage-like DCs#Immunol.2013 Nov 25;4:403CD14+macrophage-like DCs Poor T cell stimulatory abililites T cell suppressive activity Called M2-type macropha
6、ges CD1c#Immunol.2013 Nov 25;4:403CD14+macrophage-like DCs CD14+DDC(dermal dendritic cell)Poor inducers of allogeneic T cells Require high DC:T cell ratios for Th1 induction Carry low levels of co-stimulatory moleculesConvert monocyte to macrophage-like DCs IL-10,IL-6,or PGE2#Blood.2011 November 17;
7、118(20):54985505.Convert fully differentiatedDCs to macrophage-like DCs IL-10#J Invest Dermatol.2011 Feb;131(2):418-25.doi:10.1038.Convert fully differentiatedDCs to macrophage-like DCs IL-10#Int J Gynecol Cancer 2009;19:1487Y1493Convert fully differentiatedDCs to macrophage-like DCs IL-10#Int J Gyn
8、ecol Cancer 2009;19:1487Y1493Convert differentDCs to macrophage-like DCs#Immunol.2013 Nov 25;4:403Macrophage-like DCs share some striking traits Release of immunosuppressive IL-10(high)Expression of HIF1a,TGF-,VEGFA,MMP3,MMP9,IL-8,and TNFa Contribute to tumor-promoting processes Endothelial cell mig
9、ration and proliferation Tumor growth and invasion Changes that occur in myeloid cells in cancer#NATURE REVIEWS|IMMUNOLOGYVOLUME 12|APRIL 2012SIGNAL TRANSDUCTION PATHWAYS ACTING AS MASTERSWITCHES OF TUMOR-INDUCED DC SUPPRESSIONJAK2/STAT3 signaling pathway JAK/STAT signaling pathway Activated by inte
10、rferon,interleukin,growth factors JAK：Janus Kinase STAT：Signal transducers and activators of transcription#Science 296(5573):16535.doi:10.1126/science.1071545JAK2/STAT3 signaling pathway#Nat Rev Cancer.2009 Nov;9(11):798-809.doi:10.1038/nrc2734INDIRECT EVIDENCECombined STAT3 and p38-MAPKinhibition w
11、as required#OncoImmunology 1:5,649658;august 2012Combined STAT3 and p38-MAPKinhibition was required#OncoImmunology 1:5,649658;august 2012DIRECT EVIDENCE！MonocyteImmature DCMature DCM2Macrophage-like DCIL-10pSTAT3p38IL-10IL-6PEG2pSTAT3IL-10IL-6PEG2IL-10IL-10,HIF1a,TGF-,VEGFA,MMP3,MMP9,IL-8,and TNFapS
12、TAT3p38pSTAT3p38pSTAT3p38THERAPEUTIC ACTIVATION JAK2/STAT3 and/or p38-MAPK signaling interference Local immune potentiation DC-stimulatory agents GM-CSF,IL4Local immune potentiation#BLOOD,12 APRIL 2012，VOLUME 119,NUMBER 15Local immune potentiation GM-CSF,IL4 Stimulate T,B cells#J Immunol 2012;189:52
13、23-5229Local immune potentiation GM-CSF,IL4 More antibody#J Immunol 2012;189:5223-5229Local immune potentiation TLR agonists,such as LPS CpG oligodeoxynucleotidesMonocyteImmature DCMature DCM2Macrophage-like DCIL-10pSTAT3p38IL-10IL-6PEG2pSTAT3IL-10IL-6PEG2IL-10IL-10,HIF1a,TGF-,VEGFA,MMP3,MMP9,IL-8,a
14、nd TNFapSTAT3p38pSTAT3p38pSTAT3p38Referencevan de Ven R,Lindenberg J J,Oosterhoff D,et al.Dendritic Cell Plasticity in Tumor-Conditioned Skin:CD14+Cells at the Cross-Roads of Immune Activation and SuppressionJ.Frontiers in immunology,2013,4.Banchereau J,Briere F,Caux C,et al.Immunobiology of dendrit
15、ic cellsJ.Annual review of immunology,2000,18(1):767-811.Liu K J.Dendritic cell,toll-like receptor,and the immune systemJ.J Cancer Mol,2006,2:213.Obermajer N,Muthuswamy R,Lesnock J,et al.Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myel
16、oid-derived suppressor cellsJ.Blood,2011,118(20):5498-5505.Ouwehand K,Oosterhoff D,Breetveld M,et al.Irritant-induced migration of Langerhans cells coincides with an IL-10-dependent switch to a macrophage-like phenotypeJ.Journal of Investigative Dermatology,2010,131(2):418-425.Chen F,HouM,Ye F,LvW,X
17、ie X.Ovarian cancer cells induce peripheralmature dendritic cells to differentiate into macrophagelike cells in vitro.Int J Gynecol Cancer(2009)19:148793.doi:10.1111/IGC.0b013e3181bb70c6Yu H,Pardoll D,Jove R.STATs in cancer inflammation and immunity:a leading role for STAT3J.Nature Reviews Cancer,20
18、09,9(11):798-809.Oosterhoff D,Lougheed S,van de Ven R,et al.Tumor-mediated inhibition of human dendritic cell differentiation and function is consistently counteracted by combined p38 MAPK and STAT3 inhibitionJ.Oncoimmunology,2012,1(5):649-658.Vuylsteke RJCLM,Molenkamp BG,van Leeuwen PAM,Meijer S,Wi
19、jnands PGJTB,Haanen JBAG,et al.Tumor-specific CD8+T cell reactivity in the sentinel lymph node of GM-CSF-treated stage I melanoma patients is associated with high myeloid dendritic cell content.Clin Cancer Res(2006)12:282633.doi:10.1158/1078-0432.CCR-05-2431Chu C-C,Ali N,Karagiannis P,Di Meglio P,Sk
20、owera A,Napolitano L,et al.Resident CD141(BDCA3)+dendritic cells in human skin produce IL-10 and induce regulatory T cells that suppress skin inflammation.J Exp Med(2012)209:93545.doi:10.1084/jem.20112583Banchereau J,Thompson-Snipes L,Zurawski S,Blanck J-P,Cao Y,Clayton S,et al.The differential prod
21、uction of cytokines by human Langerhans cells and dermal CD14(+)DCs controls CTL priming.Blood(2012)119:57429.doi:10.1182/blood-2011-08-371245Diao J,Mikhailova A,Tang M,Gu H,Zhao J,Cattral MS.Immunostimulatory conventional dendritic cells evolve into regulatory macrophage-like cells.Blood(2012)119:491927.doi:10.1182/blood-2011-11-392894Thank you for your attention!
