Immune surveilance Flashcards
1
Q
How does the immune system play a role in cancer?
A
- immunodeficiency lead to tumour formation eg. kaposi sarcoma
- inflammatory conditions lead to cancers too eg. ulcerative colitis and colon cancer
- tumours infiltrated with lymphocytes have a better prognosis
2
Q
Can the body defend against cancer?
A
- anti-tumour immune response eg. CD8+ CTLs
- production of immune memory
- specificity of individual tumours = tumour antigens
3
Q
What are the 3 ways the immune system prevents tumours?
A
- speedy resolution of inflammation
- elimination of viral infections
- early elimination of tumour cells before they can do harm
= IMMUNE SURVEILANCE
4
Q
What is tumour immunosurveilance?
A
- process where the immune system continually recognises cancerous and pre-cancerous cells leading to their elimination before they can cause damage
5
Q
What are the 3Es of immunoediting?
A
- elimination
- equilibrium
- escape
6
Q
Define tumourigenesis
A
- normal cells undergoing change
- develop abnormal tumour antigens
- danger signals such as extra-cellular matrix products
7
Q
Describe elimination
A
- similar to old concept of immunosurveilance
- NKs, NKTs, Macs and DCs
- INFgamma and chemokines lead to tumour death
- tumour specific DCs activate adaptive immunity in draining lymph nodes
- tumour specific CD4+ and CD8+ cells join
8
Q
Describe Equilibrium
A
- elimination phase is incomplete
- tumour cells lie dormant and may modulate tumour antigen expression and stress signals
- the immune system eliminates susceptible tumour clones when possible sufficient to prevent tumour expansion
- tumour heterogeneity = darwinian selection
9
Q
What are tumour stem cells?
A
- can evade host immune surveillance
- tumour ‘seeds’
- lose MHC class I and have no NK activating ligands and silence TAA.
- can produce immunosuppressive cytokines eg. IL-4, IL-10
- selectively recruit ‘regulatory’ cells
- resistance to innate and adaptive immune response
10
Q
Describe escape
A
- immune system is unable to control the tumour growth leading to tumour progression
11
Q
Describe antigen processing and presentation
A
- some tumour cells express MHC class I/peptide complexes
- ligands to CD8+ T cells resulting in their activation and subsequent destruction of the tumour cell in vitro and in vivo
- to activate CD4+ T cells, APCs take up cell debris from tumour cells = pinocytosis, receptor mediated endocytosis
- material is processed within lysosomes and selectively bound to MHC class II molecules
12
Q
What do CD4+ T cells do?
A
- cause lymphotoxin secretion which results in direct tumour cell death
- secrete cytokines activating other cells such as NK, macrophages, CD8+ t cells
- rarely tumours themselves can act as APCs by presenting antigens on MHC class II molecules
13
Q
What are tumour antigens?
A
- produced by tumour cells can trigger immune response
- important in tumour identification and targeting in immunotherapy
- broadly classified as - tumour specific antigens = produced only be tumour cells
- tumour associates antigens - produced by tumour cells but also produced by normal cells
14
Q
What are some tumour specific antigens (TSA)?
A
- proteins of genes not directly involved in forming the tumour
eg. unique TSAs of human melanomas, MAGE-C2 peptides expressed on HLA-A2 in tumour, not expressed in germ-line cells recognised by CTLs - proteins of altered genes involved in transformation oncogenes= Ras
- tumour suppressor genes = p53
- chromosome translocations - BCR/ABL in CML
15
Q
What are tumour associated antigens (TAA)?
A
- products overexpressed genes
- Her2/neu member of EGFR family; prostate specific Ag
- cancer/testes Ags: on only normal testes
- altered membrane glycolipid and glycoprotein, Ags higher levels in tumours = altered post-transcriptional modifications
16
Q
What are the products of oncogenic virus tumour antigens?
A
- viral peptides are foreign = tumours immunogenic
- EBV - burkitts lymphoma - associated with nasopharyngeal cancer
- HPV16, 18 - associated with cervical cancer
- Hep B, C = associated with liver cancer
17
Q
What are oncofoetal antigens?
A
- inc in normal foetus
- de-repression on malignant transformation, released into serum
- markers for diagnosis and following therapy
- carcinoembryonic Ag (CEA)
- highly glycosylated, Ig superfamily member, inc. in colorectal cancer
18
Q
What is the result of down regulation and defects in antigen presentation?
A
- most healthy cells express MHC class I/peptide complexes
- in vitro studies show that tumour cells expressing tumour antigens by this mechanism get killed by CD8+ T cells
- tumours that have been selected not to express class I = survival advantage
19
Q
How is MHC class I lost from the surfaces?
A
- loss of functional beta-2 micro globulin expression
- loss of MHC class I alleles
- down-modulation of molecules involved in antigen-processing and presentation = TAP1/2, LMP2/7
20
Q
What is the result of loss of co-stimulation?
A
- melanoma cells are immunogenic but do not evolve anti-tumour immunity
- lack of CD80/86 expression on cell surface which is required for co-stimulation of T cell alongside binding
- results in T cell anergy and block IL-2 gene transcription
21
Q
What are some immunosuppressive factors?
A
- factors are either expressed/secreted by malignant cells by surrounding cells in stroma
- TGF-b = powerful, affecting nearly all cell of the innate and adaptive immune system
- VEGF - prevents maturation of DCs
- prostaglandins
- IL-10 protects tumours from tumour specific CTLs and down regulates MHC class I expression
22
Q
What are T-regulatory cells?
A
- CD4+ T cells with high expression of CD25
- 2 types =
- nTregs (Tregs developing in the thymus to ensure tolerance to self-antigens)
- adaptable Tregs (naive CD4+ T cells induced in the periphery
23
Q
How are Tregs identified?
A
- FOXP3 = winged helical transcription factor
- FOXP3 is vital for the development and function of these cells as mutations lead to severe auto-immune condition = IPEX
24
Q
Why are Tregs important?
A
- Tregs found in far greater concentrations in peripheral blood in patients with a variety of cancers
- also found in far greater quantities within tumour milieu, ascites, draining lymph nodes in patients with cancer
25
Q
What is the function of Tregs?
A
- mediate suppression on tumour specific CD4+ and CD8+ T cells via TCR
- TGF-b and IL-10 thought to be secreted in vivo and membrane bound TGFb is also highly potent
26
Q
How are Tregs targeted?
A
- anti CTLA 4
- ipilimumab
- tremelimumab
- targeting CD35 - LMB-2 fusion protein
- ontak
- conventional chemotherapy drugs like cyclophosphamide in smaller more frequent doses = deplete Tregs, enhance effector T cell function
- targeting GITR
27
Q
What are some other immunoregulatory cells?
A
- myeloid derived suppressor cells: ROS and NO suppress T cell activity
- NKT cells: produce IL-10, IL-4
- chemokines: tumour produce CCLS
