Lecture 16: Immunotherapy Flashcards
1
Q
How can the immune system contribute to the antitumour Response
A
- By destroying Viruses that are known to transform cells (viral antigens
displayed on MHC I-eg HPV and cervical cancer) - By Eliminating Pathogens to Reduce the pro-tumour inflammation
(pathogen-inflammation-cancer link). 20% of all cancers are now thought to
be associated with microbial infection. - By identifying and destroying cancerous cells mediated by immune ‘killer’
cells.
2
Q
Tumour immune profile
A
Bad vs. Good
M2 Macrophages
Myeloid Derived Suppressor Cells
(MDSCs)
Th2 cells
Treg cells
vs.
Cross-presenting APCs
NK cells
Th1
CD8+ CTL response
3
Q
Tumour escape mechanisms
A
- Loss of Tumour Ag
- Loss of MHC I or NKG2D ligands
- Loss of IFNg responsiveness (pathway defects)
- Inhibition of DC maturation/function
- Loss of costimulatory molecules (eg increase CTLA4)
- Increase Treg Activity
- MDSC
- Immunomodulatory molecules (eg IL10, TGFb IDO)
4
Q
Two classes of tumour antigens
A
Tumour specific antigens and tumour associated antigens
5
Q
Tumour-specific antigens
A
- Occur only in neoplastic cells
- Not expressed by normal cells at any site or at any stage of development
- Recognised as non-self by CD8+ CTLs
- Includes mutated cellular proteins (e.g. mutant p53, erbb family members) –
antigen processing leads to expression of novel peptides presented by
MHC class I - Virally derived antigens – HPV E6 and E7 proteins are found in 80% of
invasive cervical cancers – success of HPV vaccine
6
Q
Tumour-associated antigens
A
- TAAs are normal cellular proteins with unique expression patterns
- Only expressed at specific sites or at stages of development (e.g. fetal
development) or at very low levels in normal cells - Re-expression of fetal or embryonic genes are called oncofetal tumour
antigens (normally expressed prior to immune system acquires
immunocompetence), e.g. carcinoembryonic antigen (CEA) - 90% of patients with advanced CRC have increased CEA in their serum
- TAAs may be oncogenes that expressed at abnormally high levels – EGFR
and HER2
7
Q
Innate immune cells and the anti-tumour response- NK CELLS
A
- NK cell deficient mice increased lymphomas/sarcomas
- Chediak-Higashi Syndrome-increase in cancers-impairment in NK cells.
- NK cells Kill tumour cells:
- showing reduced MHC I expression-’missing self’ recognition by NK cells detected by KIRs (killer cell
immunoglobulin-like receptors). - NK cells kill tumours that that overexpress ligands for activating NK receptors NKG2D.
- IFNg secretion-stimulates CTL response
- NK cells also involved in ADCC (antibody dependent cell mediated cytotoxicity)
8
Q
Innate immune cells and the anti-tumour response-Macrophages M1 (Classical)
A
IFNg drives M1 phenotype-ADCC and secrete cytokines (TNFa, IL-12, IL23) which exert
cytotoxic activity on tumour cells, high MHCII/costimulatory molecules (APCs). Secrete
chemokines that lead to Th1, CTL recruitment, NK cells
9
Q
T cells and the anti-tumour response
A
- Strong anti-tumour CTL (CD8+) activity correlates significantly with tumour remission and is thought
to maintain a state of immune mediated neoplastic cell dormancy-during this period neoplastic cells
are selected that are less immunogenic to evade tumour immune response - Th1 cells secrete IFNg which promotes M1 macrophage response and IFNg increases MHC I
expression which facilitates CTL recognition of tumour antigens. - Th17 cells secrete IL-17-leads to secretion of pro-angiogenic factors-studies also show anti-tumour
effects - TILs-prognostic indicator.
- GOOD=High numbers of NK cells, CTLs is a good prognostic indicator in ovarian cancerincreased survival time.
- BAD=High Treg (freq correlates with tumour grade) and MDSCs
10
Q
B cells and anti-tumour response
A
- B cells can secrete anti-tumour antibodies
- ADCC by NK cells and macrophages
- However, B cells can block CTL response by masking
tumour antigens
11
Q
How cancer can evade the immune system
A
- Active immunosuppression in tumour environment
- Chronic inflammation
- Evasion of immune recognition and activation
- Tumour cell avoidance of apoptotic signals
- Poor co-stimulatory signals provided by tumour cells
- Expression of co-inhibitory molecules
12
Q
Active immunosuppression in tumour environment
A
- Dampening of immune response by M2 macrophages, MDSCs, Tregs and Th2 cells
- IL-4 drives M2 phenotype which release immune dampening cytokine secretion-IL-10,
chemokines which lead to Treg and Th2 recruitment. Pro-angiogenic factors (VEGF)
and growth factors (EGF, FGF) released by M2 macrophages - NK cells can be defective at tumour site
- Neutrophils secrete VEGF and proteinases elastase and MMP-8 and MMP-9
- MDSCs are immature cells comprised of precursors of macrophages, granulocytes,
DCs, and myeloid cells at earlier stages of differentiation - Tumours secrete factors to promote MDSC expansion – MDSCs induce CD8+ T cell
tolerance, block NK cell cytotoxicity, and polarize immunity toward tumour promoting
phenotype (down-regulation of IL-12 and production of IL-10)
13
Q
Chronic inflammation
A
- Increases cellular stress and can lead to genotoxic stress,
thereby increasing mutation rate - Growth factors and cytokines released by leukocytes can
also lead to increased tumour growth - Inlammation is pro-angiogenic
- Obesity and chronic inflammation – cancer link
14
Q
Tumour cell evade immune recognition and
activation
A
- Reduced MHC I/tumour antigen expression on tumour cells
- Secretion of TSAs
- Defective TAP or b2macroglobulin
- IFNg insensitivity
- NK cells should step in to kill these cells but tumour cells show
decreased expression of ligands that bind activating receptors on
NK cells
15
Q
Tumour cell avoidance of apoptotic signals
A
- Upregulation of anti-apoptotic mediators
- Down-regulation or expression of non-functioning FAS receptor on
tumour cells - Secretion of soluble form FAS receptor
