树突状细胞与肿瘤免疫研究进展.pptx

Dendritc Cells 李雨箫 Li Yuxiao 协和10级 pumc2010 学号 student ID：201001028 本文档由医学百事通高端医生网专家制作 免费咨询医生网址： Development Myeloid DC Plasmacytoid DC #NATURE REVIEWS | IMMUNOLOGY VOLUME 12 | APRIL 2012 Dendritic cells Presence of danger signals Adaptive immunity Antigen presentation Innate immunity Absence of danger signals Immune tolerance Dendritic cells Presence of danger signals Adaptive immunity Antigen presentation Innate immunity Absence of danger signals Immune tolerance Antigen presentation Kuby Immunology 6th edition Endogenous antigen Kuby Immunology 6th edition Exogenous antigen MHC II Invariant chain CLIP (Class II-associated Invariant Chain Peptide) HLADM和HLADO Kuby Immunology 6th edition Activation of T cell Signal1 Signal2 Cytokines Kuby Immunology 6th edition Dendritic Cells Not only antigen presentation! Dendritic cells Presence of danger signals Adaptive immunity Antigen presentation Innate immunity Absence of danger signals Immune tolerance Induce innate immunity IMMUNOBIOLOGY OF DENDRITIC CELLS Jacques Banchereau et al. Annu. Rev. Immunol. 2000. 18:767811 Dendritic cells Presence of danger signals Adaptive immunity Antigen presentation Innate immunity Absence of danger signals Immune tolerance Immune tolerance #Journal of Cancer Molecules 2(6): 213-215, 2006. Dendritic cells Presence of danger signals Adaptive immunity Antigen presentation Innate immunity Absence of danger signals Immune tolerance Tumor microenvironment and DCs Hot Issue Convert different DCs to macrophage-like DCs # Immunol. 2013 Nov 25;4:403 CD14+ macrophage-like DCs Poor T cell stimulatory abililites T cell suppressive activity Called M2-type macrophages CD1c # Immunol. 2013 Nov 25;4:403 CD14+ 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 molecules Convert monocyte to macrophage- like DCs IL-10, IL-6, or PGE2 # Blood. 2011 November 17; 118(20): 54985505. Convert fully differentiated DCs to macrophage-like DCs IL-10 # J Invest Dermatol. 2011 Feb;131(2):418-25. doi: 10.1038. Convert fully differentiated DCs to macrophage-like DCs IL-10 # Int J Gynecol Cancer 2009;19: 1487Y1493 Convert fully differentiated DCs to macrophage-like DCs IL-10 # Int J Gynecol Cancer 2009;19: 1487Y1493 Convert different DCs to macrophage-like DCs # Immunol. 2013 Nov 25;4:403 Macrophage-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 migration and proliferation Tumor growth and invasion Changes that occur in myeloid cells in cancer #NATURE REVIEWS | IMMUNOLOGY VOLUME 12 | APRIL 2012 SIGNAL TRANSDUCTION PATHWAYS ACTING AS MASTER SWITCHES OF TUMOR- INDUCED DC SUPPRESSION JAK2/STAT3 signaling pathway JAK/STAT signaling pathway Activated by interferon, interleukin, growth factors JAK：Janus Kinase STAT：Signal transducers and activators of transcription #Science 296 (5573): 16535. doi:10.1126/science.1071545 JAK2/STAT3 signaling pathway #Nat Rev Cancer. 2009 Nov;9(11):798-809. doi: 10.1038/nrc2734 INDIRECT EVIDENCE Combined STAT3 and p38-MAPK inhibition was required #OncoImmunology 1:5, 649658; august 2012 Combined STAT3 and p38-MAPK inhibition was required #OncoImmunology 1:5, 649658; august 2012 DIRECT EVIDENCE！ Monocyte Immature DC Mature DC M2 Macrophage -like DC IL-10 pSTAT3 p38 IL-10 IL-6 PEG2 pSTAT3 IL-10 IL-6 PEG2 IL-10 IL-10, HIF1a, TGF-, VEGFA, MMP3, MMP9, IL-8, and TNFa pSTAT3 p38 pSTAT3 p38 pSTAT3 p38 THERAPEUTIC ACTIVATION JAK2/STAT3 and/or p38-MAPK signaling interference Local immune potentiation DC-stimulatory agents GM-CSF, IL4 Local immune potentiation #BLOOD, 12 APRIL 2012， VOLUME 119, NUMBER 15 Local immune potentiation GM-CSF, IL4 Stimulate T, B cells #J Immunol 2012; 189:5223-5229 Local immune potentiation GM-CSF, IL4 More antibody #J Immunol 2012; 189:5223-5229 Local immune potentiation TLR agonists, such as LPS CpG oligodeoxynucleotides Monocyte Immature DC Mature DC M2 Macrophage -like DC IL-10 pSTAT3 p38 IL-10 IL-6 PEG2 pSTAT3 IL-10 IL-6 PEG2 IL-10 IL-10, HIF1a, TGF-, VEGFA, MMP3, MMP9, IL-8, and TNFa pSTAT3 p38 pSTAT3 p38 pSTAT3 p38 Reference van 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 dendritic 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 myeloid-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,Xie X. Ovarian cancer cells induce peripheralmature dendritic cells to differentiate into macrophagelike cells in vitro. Int J Gynecol Cancer (2009) 19:1487 93. doi:10.1111/IGC.0b013e3181bb70c6 Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3J. Nature Reviews Cancer, 2009, 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, Wijnands PGJTB, Haanen JBAG, et al. Tumor-specifi c 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-05-2431 Chu C-C, Ali N, Karagiannis P, Di Meglio P, Skowera A, Napolitano