Cancer Immunology II

Question 1

What are the different escape mechanisms of tumour cells?

Answer 1

Loss of antigenicity, no longer recognized (by MHC downregulation) or stimulation of response
Loss of co-stimulatory molecules like B7
Tumours produce immunosuppressive factors like TGFbeta and IL-10
T-cells from tumour bearing hosts are dysfunctional (tryptophan starvation)
Tumours express FasL and induce Fas-mediated CTL apoptosis
Tumours produce decoy molecules that block TRAIL-induced apoptosis

Question 2

Why is the nude mouse model no longer regarded as a perfect model for immunodeficiency, and what now is?

Answer 2

The nude mouse, while having no CTLs due its lack of a thymus actually has more NK cells than normal mice which also have anticancer activity
Instead now mice which are RAG-2 knockouts are used, these mice lack the ability to rearrange lymphocyte antigen receptors causing them to lack T, B and NKT cells

Question 3

What is the evidence for cancer immune surveillance in humans?

Answer 3

Analysis of individuals with congenital or acquired immunodeficiency or patients undergoing immunsuppression therapy show a highly elevated level of virally induced malignancies such as kaposi’s sarcoma and non-hodgkins lymphoma

Question 4

What are the three E’s of cancer immunoediting?

Answer 4

There is elimination of immunogenic cancer clones followed by an equilibrium due to iterative selection of immunoresistant variants this will eventuially be followed by escape with the expansion and uncontrolled growth of immunoresistant clones in immunocompetent hosts

Question 5

What are some of the common host elements that make up a tumour stroma?

Answer 5

Tumour infiltrating macrophages
Tumour infiltrating lymphocytes
Host fibroblasts
Vascular endothelial cells

Question 6

What are tumour associated macrophages?

Answer 6

These are the major component of host cell infiltrates into tumours and have pleitropic functions which both inhibit and promote tumour growth

Question 7

What are the functions of tumour infiltrating macrophages which inhibit tumour growth?

Answer 7

These cells can be tumouricidal, damage blood vessels, edit thrombosis or secrete immune activating factors

Question 8

What are the functions of tumour infiltrating macrophages which promote tumour growth?

Answer 8

They can secrete growth factors
Secrete angiogenic factors
Inhibit immune cells

Question 9

What is the role of tumour infiltrating macrophages in cancer progression?

Answer 9

Higher infiltrates of these cells is usually associated with poorer prognosis
Tumours secrete factors which attract the macrophages like MCP-1, M-CSF
Unlike normal tissue macrophages tumour associated macrophages proliferate in the tumour perhaps in response to GM-CSF produced by the tumour sustaining the numbers and survival of TAMs in the growing tumour
There is release of prostagalndins that’s suppress T cell and NK cell ctivity
There is also production of PDGF, TGFBeta and VEGF that promotes tumour growth and angiogenesis

Question 10

How does macrophage polarisation play a role in cancer?

Answer 10

M1 macrophages are pro-inflammatory and anti tumour they produce high levels of IL-12, IL-23 and low amounts of IL-10 this phenotype is induced by proinflammatory mediators like LPS, TNF etc, these macrophages will be efficient producers of ROS and pro-inflmmatory cytokines TNF, IL-1 and IL-6
M2 macrophages however are anti-inflammatory and protumour they produce low levels of IL-12 and IL-23 but high levels of IL-10, this phenotype is induced by Th2 cytokines IL-4, Il-13 and IL-10, TGFbeta, steroids and Vit D

Question 11

What does high levels of CD163 tell us about patient prognosis?

Answer 11

This marker is associated with M2 macrophages in melanomas and is associated with poor overall survival

Question 12

What are tumour infiltrating lymphocytes?

Answer 12

Tumours contain both CD4 and CD8 host lymphocytes, infiltration of the tumour by T cells is typically seen as a positive thing as it shows the immune system is trying to eliminate the tumour
Increased CD8 cells are associated with better survival rates
There is accumulating evidence that the immune lymphocytes do become inactivated in the tumour microenvironment however

Question 13

How does tumour mediated T cell dysfunction occur?

Answer 13

In cancer patients and some tumour bearing mice functional defects are accompanied by alterations in signal transduction, these changes appear to start at the site of the tumour and eventually become detectable in peripheral blood and splenic T cells
Dysfunction is usually reversible if the T cells are removed from the tumour microenvironment with surgical removal of the tumour allowing for normal T cell function
This suggests a factor produced in the tumour environment by either tumour cells or host inifltrates is responsible for the T cell dysfunction

Question 14

What are the defects in T cells induced by the tumour?

Answer 14

There is a decrease in the expression of the signal-transducing zeta chains
Defects in NF-kappaB activation

Question 15

How does the tumour microenvironment restrict the effectiveness of activated antitumour lymphocytes?

Answer 15

Constant stimulation through the antigen receptor in the absence of co-stimulators may lead to inactivation of T-lymphocytes
Gradual loss of Th1 cells during progressive tumour growth in mice, Th1 cells preferentially produce cytokines which stimulate T cell immunity such as IL-2 and IFN-gamma
Tumour derived MCP-1 inhibits the generation of CTL

Question 16

What is the role of Fas resistance and counter attack in immune evasion?

Answer 16

Engagement of Fas by FasL triggers intracellular events which lead to apoptosis
Fas is mainly expressed by immune cells and can be used by CTLs to kill tumour cells however these tumour cells may become resistant to this effect and then express FasL allowing them to activate the Fas o nthe immune cells and kill the CTLs

Question 17

How do tumour cells gain resistance to Fas mediated death?

Answer 17

There may be down regulation or deletion of the Fas expression
Expression of soluble Fas
Mutation into an intra-cytoplasmic Fas domain
Nutation or down regulation of caspases and other molecules involved in the Fas induced apoptotic pathway
Expression of DcR3 which is a decoy receptor capable of neutralising FasL

Question 18

What is the evidence supporting the Fas counter attack theory>?

Answer 18

T cells in the tumour microenvironment become sensitive to FasL
Apoptosis in tumour infiltrating lymphocytes is seen in FasL expressing tumours
Fas-L expressing tumour cells inoculated into Fas deficient mice develop more slowly
Two fold increase in apoptotic tumour infiltrating lymphocytes, and four fold reduction in tumour infiltrating lymphocytes in FasL positive versus FasL negative regions of oesophageal cancers

Question 19

How can changes in co-stimulatory molecules allow tumour cell evasion?

Answer 19

MHC antigens are down-regualted
Los of expression of antigens that elcit immune responses
Do not express co-stimulators

Question 20

What role does IDO play in T-lymphocyte inactivation?

Answer 20

IDO (indoleamine 2,3-dioxygenase) is the enzyme which catalyses the metabolism of tryptophan leading to low levels of the essential amino acid
T-lymphocytes are particularly sensitive to low levels of tryptophan and become inactivated
During pregnancy there is an increase in IDP expression by dendritic cells in the decidua
In mice at least IDO-mediated tryptophan starvation is a primary mechanism by which the fetus is protected from the maternal immune system

Question 21

What is the evidence that tumours use the mechanism of IDO mediated tryptophan starvation to inactivate T-lymphocytes?>

Answer 21

IDO is constitutively expressed in most human tumours
Increase in expression of IDO in dendritic cells in lymph nodes that are draining tumour sites, transfer of these IDO-DC mice into naive mice leads to inactivation of their T cells
T cell anergy could be prevent through use of IDO inhibitors