Cancer and the Immune System

Question 1

What are the most abundant stromal cells that surround tumour cells?

Answer 1

Vascular network Fibroblasts Immune cells

Question 2

Stromal cells

Answer 2

Stromal cells are connective tissue cells of any organ

• they support the parenchymal cells of that organ.

Question 3

How do stromal cells affect tumour development?

Answer 3

Stromal cells can both inhibit and promote tumour development.

• not stromal cells promote tumour growth more than they inhibit it.

Question 4

What are the key pro-tumourigenic mechanisms?

Answer 4

Anti-apoptopic Pro survival Mitogenic Pro invasive

Question 5

K-RAS mutations are implicated as being involved in what cancers?

Answer 5

Pancreatic and colorectal cancers.

Question 6

Explain the role of tumour elicited inflammation in tumour development.

Answer 6

1. Oncogene activation - leads to development of tumour cells.
2. Tumour cells activate and secrete tumour-derived factors such as cytokines and chemokines.
3. Cytokines and chemokines are inflammatory recruitment cells and recruit macrophages, dendritic cells and T/B cells.
4. The immune cells then induce further the activation of cancer cells and secrete more chemokines and cytokines.

Question 7

The destruction of cancer cells is mediated by what immune cells?

Answer 7

Cytotoxic T lymphocytes (CTLs; CD8+ T cells, effector cells).

Question 8

How do CTL’s kill cancer cells?

Answer 8

The T cell receptor of the CTL (effector cell) interacts with the MHC Class I complex expressed on the cancer cell (target cell). This activates the CTL causing it to secrete perforin which is a granzyme that hydrolyses the cancer cell membrane.

Question 9

How does the immune system recognise cancer cells?

Answer 9

CD8+ cells bind to MHC class 1 complexes on the tumour cells, with their T cell receptor.

Question 10

What do major histocompatibility complexes do?

Answer 10

They present the proteins made by a cell on the cells surface enabling it’s identification.

Question 11

Explain the steps of Cytotoxic T cell activation to destruction of the tumour cell.

Answer 11

1. The CTL’s are activated in the lymph nodes when their receptor binds to an MHC.
2. This stimulates CTL activation and maturation.
3. The cytotoxic T cell then travels to the tumour site and destroy the tumour cells by release of perforins and granzymes.

Question 12

The cancer immunity cycle - the steps needed for an anti-tumour response:

Answer 12

Question 13

Regarding the role of immunity in cancer explain the the three E hypothesis.

Answer 13

Tumour elimination

Tumour equilibrium

Tumour growth (escape)

Question 14

What are the tumour immune escape mechanisms?

Answer 14

1. Immunosupressive cells
2. Loss of tumour antigen expression
3. Inhibition of T cell infiltration
4. Inhibition of T cell activation

Question 15

What are the main immunosuppressive cells in cancer?

Answer 15

Regulatory Tcell Tregs

Myeloid derived supressor cells

Alternative activated macrophages

Question 16

What do immunosupressive cells do in cancer?

Answer 16

Immunosuppressive cells inhibit the activation and /or function of cytotoxic T cell (CTLs) in the tumour microenvironment. CTLs are no longer able to efficiently kill cancer cells.

Question 17

What are the three mechanisms that can lead to loss of antigen presentation in cancer cells?

Answer 17

1. Reduced expression of MHC Class I on cancer cells
2. Inhibition of antigen processing in cancer cells.
3. Loss of tumour antigen.

Question 18

Can cells present which MHC class recognised by what cells of the immune system?

Answer 18

Cancer cells present MHC class 1 antigens on their cell surface which are recognised by CD8+ cells.

Question 19

What are the two ways you can have inhibition of T cell infiltation?

(specifically CD8+)

Answer 19

1. Inhibition of T cell extravasation: Abnormal tumour blood vessels express molecules which kill T cells during the extravasation step. (Examples: Endothelin, Fas – Ligand).
2. Inhibition of T cell infiltration: Cancer cells induce the generation of an exessive fibrotic tumour microenvironment which acts as a physical barrier for T cells. (Examples: Fibrosis, desmoplasia).

Question 20

Define extravasation regarding inflammation.

Answer 20

In the case of inflammation, it refers to the movement of white blood cells from the capillaries to the tissues surrounding them, also known as diapedesis.

Question 21

What are the three different signals T cells need for their full activation?

Answer 21

T cells need three different signals for their full activation:

1st TCR: stimulate by epitope presented on MHC I

2nd Co-stimulatory molecule: stimulated by CD80 or CD86 ligation.

3rd activating cytokines.

Question 22

How do tumour cells inhibit T cell activation?

Answer 22

Tumour cells cells hijack the inhibitory signalling pathways preventing T cell activation.

Occurs at the immune checkpoint receptors.

Question 23

What are PD1 and CTLA4 examples of?

Answer 23

Inhibitory immune checkpoint receptors.

• inhibit T cell activation.

Question 24

PD1

What is PD1’s relevance in cancer?

Answer 24

Programmed death cell protein

Cancer cells express the ligand for PD-1 (PD-L1) to inhibit activated T cells.

Anti-PD-1 antibodies block the ligation of the PD-1 receptor on the T cell and thus the T cells remains active.

Question 25

Understand this image.

Answer 25

Understood.

Question 26

CTLA-4

What is CTLA-4’s role in cancer?

Answer 26

CTLA-4 inhibits T cell activation in the lymph node.

Question 27

Summarise what the tumour microenvironment consists of?

Answer 27

• The tumour microenvironment consists malignant cancer cells and nonmalignant stroma cells. Stroma cells are immune cells, myofibroblasts, endothelial cells, pericytes, and extracellular matrix components. Most of the stroma cells promote tumour progression.

Question 28

What is the aim of the immune checkpoint blockade?

Answer 28

Immune checkpoint blockade aims to reactivate cytotoxic T lymphocytes and thereby restores an anti-tumour immune response against cancer.