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Tumour Immunology
ESMO Preceptorship, Lund, December 2015
Nature reviews cancer April 2012
David GilhamInsttute of Cancer Sciences
The University of Manchester
Whiteside TL. J Allergy Clin Immunol 2010;125:S272-83.)
Phenotypic characteristcs of lymphocytes within tumours….
Immune suppression
T cell recogniton of tumourCell suppression mechanismsProtein / other suppressive factors
Whiteside TL. J Allergy Clin Immunol 2010;125:S272-83.)
Human Tumour Asociated Antgens
Majority are ‘SELF’ antgens
Thymic selecton
Central tolerance
Peripheral toleranceT-cell mechanismsDendritc cellRegulatory T cell
Tumour mediated suppression
Unfortunately, we all get older……
Gravekamp C.Curr Opin Immunol. 2011 Aug;23(4):555-60.Epub 2011 Jul 18.
T-cell fate under different conditions of TCRengagement.
Alegre et al. Nat Rev Immunol. 2001;1(3):220-8.
Signal 1
Signal 2
Keratin
Bw6
A-locus
A2
Keratin
Bw6
A-locus
A2
Kindly provided by Professor Peter Stern
Tumour evasion on T cell actvity: down-regulaton of HLA
The three categories of costimulatory and coinhibitorysignals at the APC-T cell interface
Ligand-receptor pairs for the B7 family, TNF family, and cytokine family of signals between the APCand T cell. Not all receptors for some B7 family members have been identfed. Some B7 familymembers interact with both costmulatory and coinhibitory receptors
Pardoll. Prendergast & Jafee (Ed):Cancer Immunotherapy, Immune Suppression and Tumour Growth. 2007.
Dong H, Chen L. B7-H1 pathway and its role in the evasion of tumor immunity. J Mol Med (Berl). 2003May;81(5):281-7. Epub 2003 Apr 30.
B7-H1 / PD-L1 expression on tumours
Surface expression of CD80 on transplantable tumor cell lines.
Tirapu I et al. Cancer Res 2006;66:2442-2450
©2006 by American Association for Cancer Research
Increased immunogenicity of cells expressing high levels of CD80.
Tirapu I et al. Cancer Res 2006;66:2442-2450
©2006 by American Association for Cancer Research
T-cell-intrinsic mechanisms of peripheral tolerance.
Walker & Abbas. Nat Rev Immunol. 2002 Jan;2(1):11-9.
Role of DCs in the choice between immunity and tolerance.
Walker & Abbas. Nat Rev Immunol. 2002 Jan;2(1):11-9.
Curotto de Lafaille MA, Lafaille JJ. Immunity. 2009 May;30(5):626-35.
Thymic and Peripheral Generaton of Foxp3+ Tregs
Vignali et al. Nat Rev Immunol. 2008 Jul;8(7):523-32.
Immunosuppressive mechanisms used by Tregs.
Treg-cell mechanisms centred around four basic modes of acton. a) Inhibitory cytokines include IL-10, IL-35 and TGF-b. b) Cytolysis includes granzyme-A- and B-dependent and perforin-dependent killing mechanisms. c) Metabolicdisrupton includes high-afnity CD25 (also known as IL-2 receptor)-dependent cytokine-deprivaton-mediatedapoptosis, cyclic AMP (cAMP)-mediated inhibiton, and CD39- and/or CD73-generated, adenosine receptor 2A(A2AR)-mediated immunosuppression. d) Targetng DCs includes mechanisms that modulate DC maturaton and/orfuncton such as lymphocyte-actvaton gene 3 (LAG3; also known as CD223)–MHC-class-II-mediated suppression ofDC maturaton, and CTLA4–CD80/CD86-mediated inducton of indoleamine 2,3-dioxygenase (IDO), which is animmunosuppressive molecule made by DCs.
Curiel et al. Nat Med. 2004 Sep;10(9):942-9.
Tumour Tregs suppress T cell actvaton in vitro.
• CD4+CD25+ Tregs fromtumour ascites, the tumourmass or blood were added tothe culture of T respondercells.
• Tumour ascites and tumourmass Tregs are as efcient asblood Tregs at inhibitng Tcell proliferaton (a) .
• Tumour ascites Tregs inhibitT cell producton of IFN-g (b)and IL-2 (c), but have noefect on IL-4 (d) or IL-10 (e)producton.
p=0.0059*
PBMC TIL
PBMC
TIL
CD4+FoxP3+ Tregs are higher in TILs thanPB of RCC
Grifths et al. Cancer Immunol Immunother. 2007;56(11):1743-53.
FOXP3
0
5
10
15
20
25
30
35
40F
OX
P3+
/CD
4+
%
Prognostc signifcance of Tregs in cancer.
Elkord et al. Expert Opin Biol Ther. 2010 Nov;10(11):1573-86.
• Tumour immunoeditng and progression include three phases, defned as: eliminaton,equilibrium and escape.
• Early in carcinogenesis T cell driven M1 actvated macrophages may contribute toeliminaton.
• During tumour progression a gradual switching of polarizaton, M1 versus M2, is paralleledby the gradual inhibiton of NF-kB actvity.
• These events concur to establish conditons for tumour growth and spread (escape phase).
Macrophage polarizaton (M1 to M2).
Mantovani &Sica. Curr Opin Immunol. 2010 Apr;22(2):231-7.
• Recent studies have identfed myeloid-origin cells that are potent
suppressors of tumour immunity.
• Together with Tregs, MDSCs promote an immunosuppressive environment
in tumour-bearing hosts.
• MDSCs accumulate in the blood, lymph nodes, and bone marrow and at
tumour sites in most patents and experimental animals with cancer
• MDSCs are induced by tumour-secreted and host-secreted factors, many
of which are proinfammatory molecules.
• The inducton of MDSC by proinfammatory mediators led to the
hypothesis that infammaton promotes the accumulaton of MDSCs that
down-regulate immune surveillance and anttumor immunity, thereby
facilitatng tumour growth.
Myeloid-derived suppressor cells (MDSCs)
Mouse and human MDSCs are heterogeneous populatons ofimmature myeloid cells.
• Subpopulatons ofMDSCs display diferentcell surface andintracellular markers andsuppress by diferentmechanisms.
• This diversity is likely dueto diferent combinatonsof factors produced byhistologically distncttumours that causemyeloid cells to arrest atdiferent stages ofdiferentaton.
Ostrand-Rosenberg & Sinha. J Immunol. 2009 Apr 15;182(8):4499-506.
MDSCs suppress anttumor immunity through a variety of diversemechanisms.
• T cell actvaton is suppressedby producton of arginase andROS, the nitraton of the TCR,cysteine deprivaton, and theinducton of Tregs.
• Innate immunity is impaired bythe down-regulaton ofmacrophage-produced IL-12,the increase in MDSCproducton of IL-10, and thesuppression of NK cellcytotoxicity.
• Ag presentaton is limited bythe expansion of MDSC at theexpense of DC.
MDSCs suppress adaptve and
innate ant-tumour immunity
Ostrand-Rosenberg & Sinha. J Immunol. 2009 Apr 15;182(8):4499-506.
Whiteside TL. J Allergy Clin Immunol 2010;125:S272-83.)
‘Tumour’ derived factors infuencing the immune system
Recognition of 30 peptides drawn from a CPL-based importance sampling set with effectivesize = 1. 66 × 108 (calculated from the sampling entropy) (second set).
Wooldridge L et al. J. Biol. Chem. 2012;287:1168-1177
©2012 by American Society for Biochemistry and Molecular Biology
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