Tumour Immunology

ESMO Preceptorship, Lund, December 2015

Nature reviews cancer April 2012

David GilhamInsttute of Cancer Sciences

The University of Manchester

Schreiber, Lloyd, Smyth (2011). Science 331(6024): 1565

Proposed theory of Cancer immunoeditng

Whiteside TL. J Allergy Clin Immunol 2010;125:S272-83.)

Phenotypic characteristcs of lymphocytes within tumours….

Whiteside TL. J Allergy Clin Immunol 2010;125:S272-83.)

…. And in the periphery

Fridman et al. Nature Reviews Cancer April 2012

Fridman et al. Nature Reviews Cancer April 2012

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

htp://info.cancerresearchuk.org/cancerstats/mortality/age/

Immune senescence / skewing of the immune response due to chronic viral infecton

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.

Differentiation of T helper cell subsets.

Zou and Restfo. Nat Rev Immunol. 2010 Apr;10(4):248-56.

Curotto de Lafaille MA, Lafaille JJ. Immunity. 2009 May;30(5):626-35.

Thymic and Peripheral Generaton of Foxp3+ Tregs

Zou. Nature Reviews Immunology 6, 295–307 (April 2006) |

Sources for Treg in the tumour??

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.

PrecursorPartally actvated / stalled / regulatory

Fully actvated / diferentated efector

Block?

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

Whiteside TL (2008) Oncogene 27: 5904-5912

Parmianiz et al. (2007). Journal of Immunology 178:1975-1979

SELF mutated antgens

Wooldridge L et al. J. Biol. Chem. 2012;287:1168-1177

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

Whiteside TL (2008) Oncogene 27: 5904-5912

Disis ML. J Clin Oncol. 2010 Oct 10;28(29):4531-8.

T-helper (Th)2 and Th1 tumour-specifc T cell immunity.