4: Immunology of cancer

Question 1

Role of immune the system: summarise evidence for the importance of tumour surveillance by the immune system, and explain how immune responses to tumours have some similarities with those to virus infected cells

Tumour antigens: explain the concept of tumour-associated antigens giving named examples, and explain how they differ from tumour-specific antigens

Immunotherapy: summarise approaches being used and developed for tumour immunotherapy, including antibody-based therapy, tumour vaccination and immune checkpoint blockade

Answer 1

?

Question 2

Evidence for importance of tumour surveillance by immune system?

Answer 2

Paraneoplastic Cerebellar Degeneration

Autoimmune disease where Immune response to breast tumour makes anti-CDR2 antibodies which goes to brain to affect neurons in cerebellum which have similar/same antigens as breast tumour cells
Destroys Purkinje cells

Question 3

What does PCD teach us?

Answer 3

1. Tumours can express antigens not expressed by normal tissue (i.e. breast tumours)
2. Immune system can detect abnormally expressed antigens and attack the tumour
3. In some cases this can result in auto-immune destruction of NORMAL tissues

Question 4

Give circumstantial evidence for immune control of tumours

Answer 4

1. Autopsies of accident victims showed microscopic colonies of cancer cells but no symptoms
2. Patients ‘free of disease’ of melanoma, after many years used as donors for transplantation. Recipients developed tumours. Suggests donor had immunity but recipient did not
3. Immunosuppression (e.g. in transplantation) increases risk of malignancy
4. Men are twice as likely to die from cancer compared to women - possibly linked to fact that women usually have stronger immune responses

Question 5

Describe the cancer-immunity cycle

Answer 5

• When tumour grows some cells die and release antigens
• These are carried by dendritic cells or other APCs via lymph to lymph node
• Antigens presented to re-circulating lymphocytes
• May activate adaptive immune response
• Activated T-cells go via blood to the tumour
• T-cells go into tumour (TIL tumour infiltrating lymphocytes)
• TILs recognise the tumour antigen (presented by MHC molecule)
• TILs kill tumour cells, releases more antigens for detection

Question 6

What are the requirements for activation of adaptive anti-tumour immune response?

Answer 6

Local inflammation in tumour

Expression and recognition of tumour antigens

Question 7

Problems with immune surveillance of cancer?

Answer 7

May take tumour a while to cause local inflammation

Difference in normal and tumour cell antigens may be subtle

Question 8

How are immune responses to tumours similar to immune responses to virus infected cells

Answer 8

In cancer T cells see ‘inside’ the cells by recognising tumour-specific antigens which are made INSIDE the cell and presented on the outside by MHC molecules

Same as viruses.

Question 9

Examples of tumour specific antigens?

Answer 9

EBV and HPV viruses often cause cancer - tumour cells present viral antigens

Mutated cellular proteins - commonly proteins involved in regulation of cell cycle

Question 10

Causes and examples of viral cancer

Answer 10

OPPORTUNISTIC - usually due to immunosuppression

EBV positive lymphoma - post-transplant immunosuppression

Kaposi sarcoma - HIV

HPV positive genital tumours (cervical cancer) -immunocompetent patients

Question 11

Proteins associated with cervical cancer?

Answer 11

E6/E7 oncoproteins of HPV

They are intracellular antigens but can be processed and presented by MHC molecules

Question 12

Target genes for HPV vaccination?

Answer 12

L1 L2 (late genes)

These are surface proteins of the virus
Incorporated into Virus-like particles

Question 13

What are tumour-associated antigens

Answer 13

Different to tumour SPECIFIC antigens
TAAs are NORMAL SELF proteins which are aberrantly expressed

Since they are normal self, tolerance may need to be overcome to achieve immune response

Question 14

Examples of TAAs

Answer 14

Cancer-testes (developmental) antigens
Found in male germ cells and placenta
e.g. MAGE family: melanoma associated antigens
Normally NOT expressed on adult tissue cells

HER2 - some breast cancers

Mucin-1 - overexpressed in many cancers

Carcinoembryonic Antigen (CEA) - normally only expressed in fetus/embryo

PROSTATE:
Prostate-specfic antigen (PSA)
Prostate-specific membrane antigen (PSMA)
Prostatic acid phosphatase (PAP)

Question 15

Example of differentiation auto-antigens?

Answer 15

Many people have poor self-tolerance to TYROSINASE enzyme (melanin production, overexpressed in melanomas)
i.e. T-cells specific for tyrosinase are poorly deleted in the thymus

Immunotherapy against melanoma in mice causes skin de-pigmentation, because there would be an auto-immune response against tyrosinase

Question 16

Problems with targeting TAAs for immunotherapy?

Answer 16

1. Can generate auto-immune responses against NORMAL tissues

2. Tumour-induced tolerance to auto-antigens

Question 17

Explain monoclonal antibody based therapy

Answer 17

1. Naked (antibody on its own) e.g. Herceptin = anti-HER2
2. Conjugated with radioactive particles or cytotoxic drug that does the damage instead of immune system
3. Bi-specfic antibodies - genetically engineered to be able to bind to 2 different antigens

Question 18

Explain cancer vaccination

Answer 18

PROVENGE for advanced prostate cancer (only approved cancer vaccine)

Patient’s WBC treated with fusion protein
Stimulates DC maturation and enhances PAP-specific T cell responses

Personalised tumour vaccine
Use RNA sequencing + WES (whole exome sequencing) on tumour cell
Use WES + HLA typing on patient’s normal cell
Identify mutations found in cancer cells
Predict peptides that bind to patient’s HLA molecules
Vaccinate against those specific antigens

Question 19

Explain Immune checkpoint blockade

Answer 19

CTLA-4: Expressed on activated regulatory T-cells
PD-1: Expressed on activated T-cells (may be upregulated in tumours)

Anti-CTLA4/PD-1 antibodies seek to reduce/remove negative regulatory signals to indirectly enhance positive immune response

Question 20

Explain Adoptive transfer of cells (ACT)

Answer 20

Take WBCs from patient with tumour
Expand Tumour infiltrating lymphocyte population in vitro
Re-infuse into patient

Question 21

Example of genetic engineering in ACT?

Answer 21

Chimaeric Antigen receptors
Can be added to T-cells
Specific to tumour antigens