Tumour Immunology

Question 1

why is the immune system not readily able to identify cancers

Answer 1

Cancers are not infectious agents so they do not have PAMPs (pathogen–associated molecular patterns) that allow the immune system to make the immune system aware of a problem.

Cancers are derived from normal cells (SELF), and our body is trained to be tolerant of normal cells. However, cancers maintain a tolerogenic state by secreting a variety of factors to maintain this tolerance

Question 2

what results in tolerance to tumour antigens

Answer 2

Lack of t cell co-stimulation

Question 3

why can cancers not recruit the adaptive immune cells to the tissues

Answer 3

As cancer cells lack PAMPs so the innate cells cannot bind them and so can’t recruit adaptive immune cells

Question 4

what cell presenting a tumour neoantigen would make it not ignored by the immune system

Answer 4

a mature dendritic cell

Question 5

how can tumours deliberately induce tolerance to make nearby dendritic cells tolerant.

Answer 5

by secreting factors such as IL-10 and VEGF

Question 6

active tolerization.

Answer 6

ability of tumors to evade or suppress the immune system (secrete other factors like TGF-beta to suppress T cell activation, proliferation and differentiation)

Question 7

what do tumours often contain which they have recruited to help the tumour cells proliferate and progress

Answer 7

many tumour-associated macrophages and neutrophils

Question 8

what does inflammation do to cancer growth

Answer 8

it drives tumour growth and angiogenesis, as tumours secrete inflammatory cytokines and chemokines (such as IL-1, IL-6, IL-8)

Question 9

what do macrophages (tumour associated inflammatory cells) produce, resulting in DNA mutations that drive disease progression and metastasis

Answer 9

reactive oxygen and nitrogen species

Question 10

what correlates with poor prognosis in 80% cancers

Answer 10

Macrophage density - macrophages support tumour growth

Question 11

2 ways tumours which produce an inflammatory environment can be treated

Answer 11

with neutralizing antibodies against the cytokines

by giving the patients anti-inflammatory drugs

Question 12

what must the tumour express for the immune system to mount an effective antitumour response

Answer 12

molecules that are not normally found within the body or fail to express molecules that are normally present on healthy cells

Question 13

Why do NK cells play an essential role in immune surveillance?

Answer 13

as MHC class 1 molecules are displayed on the surface of all nucleated cells-however failure to express MHC molecules is how NK cells select target cells for attack

Question 14

What abnormal structures on the cell surface in cancers are sometimes expressed which can affect the metastatic tumour potential

Answer 14

abnormal carbohydrate structures

Question 15

3 reasons tumours can be antigenic

Answer 15

1. Mutations - If a mutation causes a novel peptide to be generated the tumour may become immunogenic
2. some tumours re-express oncofetal antigens
3. Viruses induce some tumours. If the viral genome is incorporated into host genome, viral proteins can be made (foreign peptides)
4. if cellular proteins (MHCI) are expressed in large amounts by tumours, they can cause an immune response.

Question 16

what mutations do tumour specific antigens contain

Answer 16

tumour specific mutations

Question 17

what type of people is Kaposi’s sarcoma restricted to

Answer 17

people who are immunosuppressed due to infection with HIV

Question 18

2 things B lymphoma is caused by

Answer 18

EBV infection

patients receiving immunosuppressive drugs following organ transplantation

Question 19

how many different types of cancer/testis (CT) antigen have been defined and numbered in a CT series

Answer 19

38

Question 20

what chromosome are genes encoding 17 of the 38 CT antigens on

Answer 20

the X chromosome

Question 21

what are immune-privileged sites

Answer 21

anatomical regions that are naturally less subject to immune responses than most other areas of the body e.g. the central nervous system and brain, the eyes and the testes.

Question 22

what are tumours characterized by

Answer 22

mutations that lead to neoantigens specific to the tumour

Question 23

what do dendritic cells present tumour antigens to

Answer 23

T cells (if all goes well, the T cell will be activated and return to the tumour to kill tumour cells based on recognition of tumour-specific neoantigens or viral antigens)

Question 24

neoantigens

Answer 24

A new protein that forms on cancer cells when certain mutations occur in tumor DNA.

Question 25

dendritic cell

Answer 25

A special type of immune cell that is found in tissues, such as the skin, and boosts immune responses by showing antigens on its surface to other cells of the immune system. It is a type of phagocyte and a type of antigen-presenting cell (APC).

Question 26

Immune surveillance

Answer 26

the theory that the immune system patrols the body not only to recognize and destroy invading pathogens but also host cells that become cancerous

Question 27

what must cancer cells express for immune surveillance to work

Answer 27

must express antigens that are not found on normal cells.

Question 28

2 host gene products that are overexpressed or expressed in inappropriate cells

Answer 28

MAGE-A3

NY-ESO1 - protein produced by several types of tumours (e.g., melanoma, lung and breast cancers) but is not expressed by normal cells (except those in the testis, which is an immunologically privileged site).

HER2 - a growth factor receptor found on some tumour cells (some breast cancers, lymphomas).

Question 29

2 Host gene products that are structurally altered by somatic mutation

Answer 29

A mutated IDH1 gene, encoding the protein isocitrate dehydrogenase type 1 is frequently found in several types of cancer.

◦A mutated protein that binds with ERBB2 expressed in a carcinoma is recognized by the patient’s tumour-infiltrating lymphocytes (TILs), and these Th1 cells can destroy the tumour cells.

Question 30

what are immunodeficient Mice

Answer 30

Mice with genes needed to make Th1 cells and/or cytotoxic T lymphocytes (CTLs) and/or NK cells knocked out (have an increased incidence of spontaneous tumors and are more susceptible to getting tumors from chemical carcinogens.

Question 31

what holds malignant cells in check in healthy mice when they are given low dose of chemical carcinogen

Answer 31

the adaptive immune system

Question 32

2 examples of immunodeficient humans

Answer 32

AIDS patients

Transplant recipients -
elevated incidence of cancers such as Kaposi’s sarcoma (AIDS) and B-cell lymphomas (in both AIDS patients and transplant recipients).

Question 33

Immunocompetent Humans

Answer 33

Cancer patients whose tumors contain large numbers of tumor-infiltrating lymphocytes (TILs), e.g., Th1 cells and/or cytotoxic T lymphocytes (CTLs) and/or NK cells cope with their disease better than patients with only small numbers of these cells

Question 34

what leads to rare immune surveilance failures

Answer 34

a cell may acquire somatic mutations in uncontrolled mitosis path t0 increasingly protect it from attack by the host’s immune system

Question 35

3 e.gs of somatic mutations that increasingly protect cells from attack by the host’s immune system

Answer 35

reduced expression of tumour antigens

reduced expression of class II MHC molecules needed to display tumour antigens to CD4+ Th1 cells

reduced expression of class I MHC molecules needed to display tumour antigens to CD8+ cytotoxic T lymphocytes (CTLs)

secretion of immunosuppressive cytokines (e.g., Transforming Growth Factor-beta — TGF-β)

recruitment of immunosuppressive Treg cells.

Question 36

what is interferon gamma produced by

Answer 36

antigen activated TH1 cells

Question 37

What does interferon gamma do, in addition to its antiviral affects

Answer 37

IFN gamma enhances MHC class 1 on many cells and increases MHC class II and B7expression on B cells and macrophages, thereby enhacing antigen presentation.

Question 38

What does IL-12 do?

Answer 38

It activates NK cells

Question 39

3 main ways that the cancers are immunosuppressive

Answer 39

Reduced antigen processing and presentation (are fewer MHC (HLA) molecules to present the tumour peptides to the TCR)

Anergic T cells-t cells that cannot respond to their specific antigen –they increase the production of co-inhibitory recepetors so that T cells are inhibited

the tumours produce cytokines which lower the immune response to the tumour

Question 40

immunoediting

Answer 40

a selection pressure for cancer causing mutations to be immunologically silent by IS (makes them not strongly immunogenic)

Question 41

how can TAP proteins make immune surveillance fail

Answer 41

due to a reduced efficiency of loading antigenic peptides into MHC molecules by TAP proteins

Question 42

what does TGF-beta (immunosuppressive cytokines) prevent the proliferation of

Answer 42

both B and T cells (essential in controlling immune reactivity)

Question 43

what do many solid tumours secrete that promote angiogenesis

Answer 43

vascular endothelial growth factor (VEGF)

Question 44

5 ways how tumour cells can evade destruction by cytotoxic T cells

Answer 44

Modification of tumour microenvironment (secretion of immunosuppressive cytokines like TGF-β)

Modification of immune cell repertoire by stimulation of immunosuppressive response

Loss or mutation of MHC class I on tumour cells

Exploitation of immune-checkpoint proteins

Increased CTLA-4 expression on T cells (counteracts CD28)

Increased PD-1 expression on T cells

Question 45

3 ways tumour cells evade immune response

Answer 45

Downregulate intercellular adhesion molecule 1 (ICAM-1) and LFA-3 to decrease CTL conjugate formation.

Tumour cells express CD99 which downregulates NK CD16 and the growth inhibitor RCAS1, which induces apoptosis in NK and CTLs.

Tumours can decrease their vulnerability to CTL attack by expression of surface FasL and a growth inhibitory molecule, RCAS1, which react with T cells, stopping them in their tracks.

Tumours secrete immunosuppressive factors such as TGF-beta and IL-10

Natural regulatory T cells (Tregs) that normally guard against autoimmunity may also prevent T cell responses against tumours.

FasL on tumour cells can resist attack by the Fas positive CTLS