L19- Cancer Immunology

Question 1

What is cancer caused by?

Answer 1

The progressive growth of the progeny of a single transformed cell

Question 2

What are the aims of cancer therapy?

Answer 2

Remove or destroy the cancer cells, specifically without damaging healthy cells

Question 3

What is cancer immunotherapy?

Answer 3

Boosting the immune response against the tumour, it is specific and could spare healthy cells

Question 4

What are the different immunotherapy strategies?

Answer 4

• Adoptive T cell transfer
• Vaccination
• Monoclonal antibodies against tumour antigens
• Monoclonal antibodies against T cell inhibitory receptors

Question 5

What is the cancer immunity cycle?

Answer 5

• APC’s present tumour antigens in lymph nodes
• Antigen specific CD4+ and CD8+ T cells become activated and travel to tumour sites
• They scan for target cancer cells displaying cognate Ag and kill them

Question 6

What are the 4 different categories of tumour antigens?

Answer 6

• Antigens encoded by genes specifically expressed by tumours
• Antigens encoded by variant forms of normal genes altered by mutations
• Antigens normally expressed at certain stages of differentiation
• Antigens over-expressed in particular tumours

Question 7

What are the immune responses to tumours?

Answer 7

• NK cell activity
• Macrophage mediated tumour destruction
• ADCC
• T-cell mediated lysis

Question 8

What are the mechanisms by which tumours avoid immune recognition?

Answer 8

• Low immunogenicity
• Tumour treated as self antigen
• Antigenic modulation- loss of antigen after treatment with antibodies
• Tumour induced privileged site- barrier to immune system

Question 9

What is tumour-induced immune suppression?

Answer 9

Factors like TGF-b secreted by tumour cells inhibit T cells by inducing regulatory T cells

Question 10

How do tumour cells inhibit immune checkpoints?

Answer 10

• Exploit inhibitory receptors and ligands that impair T cell survival, activation, proliferation and effector functions.

Question 11

What is ICB immunotherapy?

Answer 11

• Immune-checkpoint blockade immunotherapy

* Target and block immune checkpoint molecules to unleash anti-tumour responses e.g CTLA-4, anti PDL1 drugs

Question 12

What are CTLA-4 and PD-1

Answer 12

• Co-inhibitory molecules which localise to immune synapse to down-modulate T-cell signalling and responses
• Strong expression of these molecules can prevent effective immune synapse signalling
• T-cell activation triggers their expression (negative feedback)

Question 13

What is the role of CTLA-4?

Answer 13

• Inhibits co-stimulation by CD28 with which it shares ligands CD80 and CD86
• Higher affinity for CD80 and CD86 so it outcompetes CD28 binding and dampens co-stimulation
• Central role in maintaining immune tolerance in lymph nodes
• Not expressed until T-cell undergoes antigen recognition
• Rapidly mobilised to cell surface from intracellular protein stores

Question 14

What is the role of PD-1?

Answer 14

• Only expressed after TCR engagement
• Expression requires transcriptional activation- slower
• Expression activates inhibitory phosphatase PP2A
• Directly inhibits TCR-mediated effector function
• Restrains collateral tissue damage during T cell responses to infection

Question 15

What are PD-1 ligands?

Answer 15

• PDL1- induced on activated haematopoietic stem cells by IFN-g
• PDL2- expressed on DC’s and some macrophages

Question 16

What are the two mechanisms of PDL1 induction in cancer?

Answer 16

1. Intrinsic resistance- refers to constitutive expression of PD-1 ligands because of genetic alterations or activation of oncogenic pathways in cancer cells
2. Adaptive resistance- Induction of tumour PDL1 expression in response to IFN-g by T cells

Question 17

What are the mechanisms of immunosuppression via PDL1?

Answer 17

• T cell exhaustion
• T cell apoptosis
• T-reg induction