Cancer Immunobiology

Question 1

Describe the function of the immune system

Answer 1

The immune system is a collection of organs, cells, and processes that protect us against infection, illness, and disease. The immune system fights off foreign invaders, but cancer cells are endogenous, so how does it know?

Question 2

Describe the different types of treatment for cancer

Answer 2

Surgery - optimum for ear, localised cancer. Often in combo with radio/chemo
Chemotherapy - Usually in combo with other treatments, not curative for most solid cancers alone.
Radiotherapy - High energy radiation to destroy cancer cells, or impede growth. Usually beamed through the skin, but can place radioactive source internally
Immunotherapy - Drug treatment that empowers the body’s immune system to attack cancer.

Question 3

Explain what is meant by a tumour cell antigenins

Answer 3

Antigens are substances that are able to cause an immune response. Tumour cell antigens are cell surface antigens usually membrane proteins or processed cytosolic proteins. Normally, these antigens havent been exposed in significant amounts to the immune system, however in tumours this changes because theyre made at much larger quantities, at wrong developmental stage, or modified differently

Question 4

What are the main groups of tumour cell antigens?

Answer 4

Tumour Specific Antigens - Present ONLY on tumour cells
Tumour Associated Antigens - Can be expressed at high levels on tumour cells but not exclusively
Oncofetal Antigens - Only present on normal cells in fetal development

Question 5

Describe how tumour-specific antigens can develop

Answer 5

Mutations in the genome of the cancer cell lead to modified proteins which are processes, and novel peptides (TCAs) are produced, which can induce a cell-mediated immune response by cytotoxic t cells.

Question 6

Describe how oncoviruses can result in tumour-specific antigens

Answer 6

The viral oncogenes can generate neoplastic host cell transformation. These genes may be immediately expressed or integrated into the DNA and expressed later. Virally induced tumour antigens are coded for by the virus, so all cells infected by that virus will have the same antigens

Question 7

Explain how Tumour Associated Antigens can arise

Answer 7

The amplification of antigens can be caused by DNA mutations, viral infections, genetic disorders. Also, glycosylation is altered in many tumours

Question 8

Describe the characteristics of Oncofetal antigens

Answer 8

Antigens that are usually only present in fetal development become reactivated in adult tumour cells, becoming effectively a TSA eg. Carcinoembryonic antigen (CEA) and a-fetoprotein (AFP). CEA is expressed on colon cancer cells and epithelial tumours, AFP on liver cancer cells

Question 9

How do viruses contribute to cancer?

Answer 9

15-20% of cancers are from oncoviruses. Immune systems eliminates most cancer promoting mutation carrying cells but some slip through. Oncoviruses can be DNA or RNA.

Question 10

In which ways can viruses cause cancer?

Answer 10

Chronic inflammation - In an immune response, inflammation arises, but chronic inflammation can increase proliferation to replace damaged cells. This rapid proliferation results in increased amounts of mutations, causing cancer
Viruses can directly damage DNA
Viruses can alter the immune system’s ability to fight cancer

Question 11

How does a DNA Oncovirus cause cancer?

Answer 11

They integrate their DNA into the genome of the hosts cell, which leads to oncogenic transformation of the cell

Question 12

What is immune surveillance?

Answer 12

Immune surveillance is the theory about how immunity not only protects us from infectious agents but also recognises and destroys abnormal/mutated cells.
Paul Enrich’s theory is that our immune response continuously reacts against cancer cells as fast as they appear. Lewis Thomas suggested that the immune system recognises newly arising tumours through expression of TSAs and eliminating them, maintaining tissue homeostasis in complex multicellular organisms

Question 13

List some evidence that supports the immune surveillance theory

Answer 13

Post transplant patients on immunosuppressants show higher occurance of EBV+ large B cell lymphomas
Patients with AIDS (HIV infected) have higher occurence of Kaposi’s sarcoma and EBV+ B cell lymphomas
Young and old people have higher incidence of tumours

Question 14

List some evidence that goes against the immune surveillance theory

Answer 14

Nude mice (lacking T cells and thymus) don’t get cancer
Immunosuppressed patients have higher occurence of some cancers but not common ones
Theory assumes there’s only a qualitative difference between normal and tumour cell antigens
Assumes cancer cells only develop when immune system is impaired, or if cancer cells lose their ability to provoke an immune response (immunogenicity), allowing them to escape immune surveillance

Question 15

What role do APCs have in immune surveillance?

Answer 15

Phagocytose TCAs and display the processed peptide fragments bound to MHC molecules on their surface. Interactions between MHC and TCR is in the first signal for T cells to attack cancer cells.
Second signal is the interaction between costimulatory molecules on T cell and APC surface membrane eg CD28 (T cell) and CD80/86 on APC. Most common APCs are dendritic cells, B cells, macrophages

Question 16

What role do T cells have in immune surveillance?

Answer 16

They are activated by APCs to identify and remove cells with foreign antigens. The main types are helper T cells and cytotoxic T lymphocytes. Immature cytotoxic T cells are activated by recognition of MHC complex, undergo clonal expansion (some going to memory cells) and then attack cancer cells and die

Question 17

What is tumour immune editing?

Answer 17

The explanation as to how tumours still exist despite an immune response. It involves 3 stages

Question 18

What is the immune surveillance/elimination stage of tumour immune editing?

Answer 18

When cancer cells are killed by the immune system

Question 19

What is the equilibrium stage of tumour immune editing?

Answer 19

When not all the cancer cells are killed, and the immune system and cancer cells are balanced. The cancer cells remain dormant or keep mutations that can lead to altered antigens no longer recognised by the immune system. This phase can last for years. Also, there’s a balance between tumour promoting (IL10/23) and anti tumour (IL12, IFN-y) cytokines.

Question 20

What is the escape stage of tumour immune editing?

Answer 20

When the immune system can’t control the growth of the tumour and the cancer cells expand. This is where clinical malignancies can emerge. Tumour cells can also evade recognition by immune checkpoint activation

Question 21

What are immune checkpoints?

Answer 21

Immune checkpoints are important regulators of the immune response, normally functioning to prevent autoimmunity. On T cell surface membrane, there are many immune checkpoint receptors (PD-1, CD28, CTLA-4). PD-1 seeks out PD-1 ligand on other cells to determine if they are healthy or not.

Question 22

How do immune checkpoints function in cancer?

Answer 22

Normally, activated T cells will kill cancer cells with antigens that they were activated by (in the MHC complex). The immune checkpoint ligand being present in the tumour cell surface membrane allows them to inactivate the T cells. Enhancing anti tumour immunity may come from blocking the immune checkpoint receptors.

Question 23

What is the purpose of a cancer vaccine?

Answer 23

To stimulate the immune system into being able to recognise the cancer cells as abnormal and destroy them

Question 24

What are the two different types of cancer vaccines and their function?

Answer 24

Preventative (prophylactic) - Prevent cancer from developing in healthy people
Treatment (therapeutic) vaccines - Treat an existing cancer by strengthening the body’s immune system

Question 25

Explain how a dendritic cell vaccine works

Answer 25

Dendritic cells from the patient are extracted, and GFs introduced, then the cells are exposed to antigens from the patients cancer cells, and then injected back into the patient

Question 26

Explain how antigen vaccines work

Answer 26

TSAs are injected into the cancerous areas in the patient, usually along with an immune stimulant, and then the immune system creates cytotoxic T lymphocytes which will attack the cancer cells with the same antigen. Can be performed with multiple antigens

Question 27

Explain how DNA vaccines work

Answer 27

DNA from the patient’s cells is injected into the patient, and this DNA tells other cells to continuously produce certain antigens. . This results in the production of more T cells. The vaccine is generally injected into skin or muscle, where the antigen is expressed in myo/keratinocytes and transferred to DCs via cross presentation (indirect route), some DNA is also directly taken up by DCs (direct route). DNA vaccines are cost effective, administered rapidly and offer long term protection, also well tolerated with not many adverse effects

Question 28

Explain how tumour cells vaccines work

Answer 28

Cancer cells removed from patients during surgery are irradiated and altered in the lab, aiming to increase their immunogenicity. They’re then injected into the patient. Two advantages are that they have all the relevant antigens to mount an immune response, and it allows development of cancer vaccines without knowing the specific antigens

Question 29

How does a HPV vaccine work?

Answer 29

The HPV L1 major capsid protein of the virus antigen is used for immunisation, and expression of this protein uses recombinant DNA technology. L1 protein self assembles into non-infectious virus like particles which resemble HPV virions, and they produce long lasting high levels of antibodies

Question 30

What are bivalent vaccinations?

Answer 30

A type of vaccination that stimulates a response against two different antigens, also have quadravalent and 9-valent

Question 31

What are side effects of cancer vaccines?

Answer 31

Inflammation at injection site (redness, pain, swelling, warm, itch, rash). Sometimes flu-like symptoms (fever, chills, weak, dizzy, nausea, vomiting, muscle ache, fatigue, headache, breathing difficulty). Short lived effects, shows body is mounting an immune response

Question 32

What is CAR T cell therapy?

Answer 32

A therapy that combines the effector functions of T cells and the ability of antibodies to recognise pre-defined surface antigens with a high degree of specificity in a non-MHC restricted manner

Question 33

What is the structure of a CAR?

Answer 33

It’s a fusion protein composed of an extracellular domain, for tumour antigen recognition, derived from an antibody. Also one or more intracellular signalling domains that mediate T cell activation

Question 34

How can CAR T cells kill cancer cells?

Answer 34

They utilise the granzyme and perforin axis to specifically lyse the antigen positive tumour cells
CAR T cell-derived cytokines can sensitise the tumour stroma. Driving IFN-7 receptor upregulation facilitates stromal cell targeting by IFN-7
Also, the antigen negative fraction of a tumour can be targeted by CAR T cells via Fas and Fas L

Question 35

What are the advantages of CAR T cell therapy?

Answer 35

MHC independent antigen targeting, induction of T cell expansion upon interacting with antigen, high affinity binding, enables production of high numbers of antigen specific T cells

Question 36

What are the disadvantages of CAR T cell therapy?

Answer 36

Low persistence in vivo, antigen cross reactivity, immunosuppressive tumour microsensitive can impair function, requires patient’s t cell engineering, requires optimal t cell to target cell spacing distance for t cell activation

Question 37

How can immune checkpoint inhibitors be used to treat cancer?

Answer 37

Some cancer cells express ligands that can bind co-inhibitory receptor molecules (immune checkpoints) that usually maintain self tolerance. Immune checkpoint inhibits act by regulating these pathways to enhance the anti-tumour response

Question 38

What are advantages of immune checkpoint therapy?

Answer 38

It is non cancer type specific, and induces a potent anti-tumour immune response

Question 39

What are disadvantages of immune checkpoint therapy?

Answer 39

There is a risk of immune-related adverse events, and depends on the immune status of patients, and cancer cells can undergo complex immune evasion strategies

Question 40

What is adoptive T cell therapy?

Answer 40

When lymphocytes are expanded and modified ex vivo and reinfused back into the patients. Consists of tumour infiltrating lymphocytes, CAR T cells, T cell receptor transduced T cells, and gamma delta T cell adoptive therapy

Question 41

What are ab T cells?

Answer 41

They are composed of two glycoprotein chains (TCR chains), and they are the main population of circulating lymphocytes, and have the role of recognising the peptides in the MHC complex

Question 42

What are gamma delta t cells?

Answer 42

Have one gamma chain and one delta chain. They make up 1-10% of peripheral lymphocytes. They share many qualities with their ab T cell counterparts. They are able to recognise antigens independent of MHC molecules - activated by phosphoantigens. They can act as APCs

Question 43

What is gamma delta t cell therapy?

Answer 43

This therapy has a potent antitumour effect in pre-clinical studies. It is safe and well tolerated.