Immune Context of the TME

Question 1

Tumours contain what different parts?

Answer 1

Cancer cells, stromal cells, ECM and immune cells

Question 2

Production of what regulates the TME?

Answer 2

Growth factors, cytokines and chemokines

Question 3

What does the TME promote?

Answer 3

Growth, chemo resistance, surpression of the cancer specific immune response

Question 4

Innate immunity cells are?

Answer 4

Rapid

Question 5

Adaptive immunity cells are?

Answer 5

Slow

Question 6

How do immune cells kill cancer?

Answer 6

When a cancer cell dies, antigens are released that the immune system detects using its dendritic cells. These prime and activate T cells that are trafficked to the site of the tumour. T cells infiltrate the tumour and stroma, recognise cancer cells and kill them.

Question 7

The tumour microenvironment tries to prevent…

Answer 7

T cells getting to the tumour and recognising the cancer cells

Question 8

Which T cells are key effectors for the anti-cancer response?

Answer 8

CD8 T cells

Question 9

What do CD8 cells do to tumours?

Answer 9

Clear the primary tumour and travel in fluids to the distal sites too and prevent future regrowth.

Question 10

Because of the role of CD8 cells, therapies try to do what?

Answer 10

Make CD8 cells work more effectively.

Question 11

T-cell infiltration is a indicator of what?

Answer 11

It’s an indicator of good prognosis

Question 12

What’s important about using T-cell infiltration as a prognostic indicator?

Answer 12

The cell types are important. CD8 and TH1 cells are good, others in the TME are not so good.

Question 13

TH1 cells do what?

Answer 13

Helper T cells produce cytokines to encourage apoptosis and prevent proliferation, and they push the CD8 response.

Question 14

Why do T cells infiltrate some cancers better than others?

Answer 14

The genetic instability of cancer leads to more abnormal antigens being presented over time. Some antigens just have a high tumour specificity, some are shared with normal tissue, some are just increased in amount but would be present anyway.

Question 15

High mutation rate = higher T cell infiltration due to more antigens. Which tumours tend to have high mutational burden?

Answer 15

Lung and melanoma etc.

Question 16

Why are subclones an issue for our T cells

Answer 16

It might only be some cells expressing a neoantigen because it’s from a branch mutation, so these might be worse targets for our T cells if they want to remove the whole cancer

Question 17

Low levels of mutational heterogeneity leads to…?

Answer 17

Better response to therapies that activate T cells.

Question 18

What are the 3 E-phases of cancer immune editing?

Answer 18

Elimination phase, Equilibrium phase and escape phase

Question 19

What is the Elimination phase?

Answer 19

Malignant cells killed early during transformation by immune surveillance

Question 20

What is the equilibrium phase?

Answer 20

Some tumour cells survive the initial onslaught from the immune system, then undergo a period of editing whereby resistant clones are selected for

Question 21

What is the escape phase?

Answer 21

Edited tumour cells escape control due to immune evasion or suppression. They proliferate and form a mass.

Question 22

Immune evasion is a …

Answer 22

hallmark of cancer

Question 23

The immune contexture of the TME creates an inter-regulated dynamic signalling network producing what that the T cells need to dodge?

Answer 23

Many things! The TME produces cytokines, chemokines, enzymes, small molecule, and signal to suppressive cells to try and turn off CD8 cells

Question 24

What are the other immune cells that act to supress CD8 cells through signalling molecules called?

Answer 24

Tumour associated macrophages, Myeloid-deprived suppressor cells, regulatory T cells (Treg)

Question 25

Macrophages show plasticity and variability. What are M1 and M2?

Answer 25

M1 - Immunostimulatory.
M2 - (Tumour associated macrophage) recruits Treg cells, produce enzymes, secrete cytokines.

Question 26

Myeloid derived suppressor cells do what?

Answer 26

Supress CD4 and CD8 cell function, and recruit Treg cells.

Question 27

What do Treg cells do?

Answer 27

Release inhibitory cytokines to turn off or kill effector cells.
Cause cytolysis of T cells.
Cause metabolic disruption of T cells leading to death.
Target dendritic cells, inhibit maturation and function.

Question 28

Macrophage populations in the TME can correlate with what?

Answer 28

Prognosis. Lots of M2 is bad. M1 is good.

Question 29

Immune cells have lots of co-stimulatory and co-inhibitory receptors. These are coordinated via interactions with antigen-presenting cells. This whole arrangement does what?

Answer 29

Creates Immune checkpoint - regulatory pathways the prevent excessive stimulation of the immune response

Question 30

PD-1 is a receptor, where is it expressed?

Answer 30

On the surface of T cells

Question 31

What does PD-L1 do when binding to PD-1 receptor on T cells.

Answer 31

It’s on the surface of some immune cells, and tumour cells. It inhibits T cell receptor signalling, inducing anergy/death

Question 32

So a T cell can recognise an antigen on a tumour, be costimulated to become fully active, and then what can stop it all?

Answer 32

An inhibitory signal from PD-L1 slams on the brakes

Question 33

How do we go about using therapy to target the PD-1 PD-L1 interaction?

Answer 33

Use antibodies that block the interaction, so the CD8 T cells are not exhausted and will stay active and kill the tumour cells.

Question 34

What effect does Anti-PD-1 have on the evolution of the immune population in the TME?

Answer 34

Down regulation of metabolism, increased T cell activation and function

Question 35

What is an immunologically hot or cold tumour?

Answer 35

Hot - High T cells, neoantigens present, expressed PD-L1. Can be targeted by immune checkpoint inhibitors.
Cold - Few neoantigens so few T cell infiltration, little PD-L1.

Question 36

What are other aspects of the TME you can target with drugs other than immune checkpoint inhibitors?

Answer 36

IFN signalling, gene signatures, physical factors, cell infiltration, changing the M type of Macrophages from 2 to 1.