Week 13 Part 2 - Cancer Immunology

Question 1

Most Common Cancers in Men

Answer 1

Prostate cancer > lung cancer > colon, rectum

Question 2

Most Common Cancers in Women

Answer 2

Breast cancer > lung, colorectal > uterine cancer

Question 3

What Causes Cancer

Answer 3

DNA is exposed to radiation, chemicals, viruses, part of aging process
DNA breaks and recombines incorrectly or mutates
Cell produces
- unusually large amounts of normal proteins
- an altered form of that protein
- no protein

Question 4

Tumour Specific Antigens

Answer 4

Antigens (over)expressed by the tumour
Can lead to anti-tumour immunity
Tumour antigens can be used for:
- diagnosis
- targets for immunotherapies

Question 5

Evidence of Cancer from Organ Transplants

Answer 5

Transplant patients - higher rate of cancer than general public
Melanoma - 0.3% general paediatric pop. versus 4% in paediatric transplants
Sarcoma - 3-fold higher risk in transplant patients
Lung carcinoma - 25-fold increase in cardiac transplant patients

Question 6

Evidence that the Immune System can Destroy Tumour Cells

Answer 6

Some tumours spontaneously regress
Better prognosis if tumour infiltrating lymphocytes present
Tumours employ escape mechanisms to avoid immune destruction
Cytotoxic T cells & NK can kill tumour cells

Question 7

Generating an Anti-Tumour Response

Answer 7

1. Cell has mutated and is uncontrollably dividing taking over the tissue site
2. DCs take up tumour cell and travel to lymph node
3. Presents to naive T cell that has to have specific TCR
4. Activation/production of tumour specific T cells which travel back to tumour tissue

Question 8

CD8+ Cytotoxic T Cells - Role in Tumour Regression

Answer 8

Lyse cells expressing a specific antigen presented in MHC class I molecules
Release perforin, granzyme and FAS-FAS Ligand interactions

Question 9

Why is the Immune Response to Tumours
Ineffective?

Answer 9

Tumour antigen/s are never presented to T cells
- ignorance
Tumour antigens are presented to T cells but:
- T cells are unresponsive (anergised/tolerised)
- the response is inappropriate - too little, too late
- T cells are induced to die (apoptosis)
- T cell (subsets) are unable to enter the tumour
- T cell responses are limited to a single epitope
- T cells express checkpoint molecules and/or their ligands
- tumour cells and infiltrating innate cells express checkpoint molecules and/or their ligands which can shut down T cells

Question 10

Evading the Immune Response - Immunosuppresion

Answer 10

Tumour cells secrete suppressive cytokines e.g. TGFb, VEGF
Regulatory cells secrete suppressive cytokines e.g. TGFb, IL-10
- CD4+CD25+FOXP3+ T regulatory cells
- M2 macrophages
- myeloid-derived suppressor cells
Evading the immune response
‘Hide’ -> No MHC class I = cannot be a CTL target
No danger signal
- tumour cells do not initiate inflammation - e.g. no TLR activation
- tumour cells can present antigen - but no co-stimulation molecules

Question 11

Three E’s of Cancer Immunoediting

Answer 11

Elimination
Equilibrium
Escape

Question 12

Tumour Elimination

Answer 12

Innate cells recognise tumour establishment
Dendritic cells transport tumour antigen to LN
Tumour-specific T cells home to tumour site
Eliminate tumour cells

Question 13

Tumour Equilibrium

Answer 13

Tumour-specific T cells home to tumour
Cannot completely eliminate tumour cells
Tumour cells avoid killing by genetic alteration
- lose tumour antigen
- downregulate MHC class I molecules
- secrete soluble factors that disable the immune system
- recruit regulatory cells into the tumour microenvironment

Question 14

Current Therapies

Answer 14

Surgery - aims to remove the cancer
Chemotherapy and radiation - aims to directly kill cancer cells
Can be successful if cancer caught early enough
- but recurrences often occur after 5 years
- can have severe side effects

Question 15

Cancer Immunotherapy

Answer 15

Aims to bolster the immune system so that it kills cancer cells

Question 16

Cytokine Therapy - Interferons IFNa, IFNb, IFNg

Answer 16

Stimulate NK, T cells & macrophages
IFNg limits “Hairy” cell leukemia’s

Question 17

Cytokine Therapy - Tumour Necrosis Factor

Answer 17

Directly attacks & kills tumour cells
Tested alone & in conjunction with IFNg

Question 18

Cytokine Therapy - IL-2

Answer 18

Promotes CTL, NK & macrophages
Toxic
Effective -> melanoma, renal cancer

Question 19

Cancer Vaccines

Answer 19

Based on tumour antigens
Aims to stimulate an immune response to a specific type of cancer:
- used to treat cancer patients
- may be used to prevent cancers developing

Question 20

Tumour Cell-Based Vaccines

Answer 20

Injection with (usually irradiated)
- autologous tumour, from surgical resection or biopsy specimens
- allogeneic tumour from cell lines
Tumour cells modified => more immunogenic
- transduced with genes expressing cytokines or co-stimulatory molecules
Responses disappointing

Question 21

Adoptive Transfer of Tumour-Specific Cytotoxic T Cells

Answer 21

Viruses used to insert genetically engineered genes into T cells
Genes code for antibodies that target a tumour antigen (antigen receptor)
T cell expressing the chimeric antigen receptor (CAR) on their surface are expanded
CAR T cells transferred back into the patient identify and destroy cancer cells

Question 22

Dendritic Cell Vaccines

Answer 22

Blood & bone marrow DC readily accessible
Can generate large numbers in vitro
Can manipulate in vitro
- expose to tumour antigens
- genetically modify
- activate
Returned to host
Stimulate anti-tumour effector CTL

Question 23

Pros and Cons of DC Vaccines

Answer 23

Feasible & safe
BUT tolerance occurred when immature DC given to patients
Clinical responses in 10-20% of patients (more common in melanoma)

Question 24

Anti-Tumour Antibodies - Monoclonal Antibodies

Answer 24

Developed over the last 30 years
Highly specific
Target tumour antigens
Can be mass produced

Question 25

Problems with Monoclonal Antibodies

Answer 25

Antibody penetration into tumour mass may be poor
Antibodies from mice immunogenic -> anti-mouse response -> limits anti-tumour activity
Can now readily “humanise” antibodies
Takes >10 years to develop

Question 26

Checkpoint Molecule CTLA-4

Answer 26

CTLA-4 on T cells
Competes with CD28 also on T cells for B7 on APCs
CD28 binds to B7 = T cell activation
CTLA-4 binds B7 = inhibits T cell activation and proliferation
CTLA-4 has higher affinity for B7 than CD28

Question 27

Monoclonal Antibodies that Target Checkpoint Molecules - Anti-PD-1

Answer 27

Normally, PD-L1/PD-1 binding inhibits T cell killing of tumour cell
Anti-PD-1 blocks PD-L1 or PD-1 and allows T cell killing of tumour cells
Prevent the PD-1/PDL-1 pathway from suppressing anti-tumour T cells
Anti-PD-1 is superior and better tolerated than anti-CTLA-4