Transplantation and Tumour Immunology

Question 1

Forms of allograft rejection - onset, immune cells involved, prevention method

Answer 1

Hyperacute
Acute
Chronic

Question 2

Factors triggering transplant rejection - source, mechanism, prevention

Answer 2

Foreign HLA molecules
Pre-formed Ab against the graft - anti-donor HLA Ab from previous exposure or anti-ABO Ab
MiHA

Question 3

Immunosuppression - purposes (3), drugs involved, risks/side effects

Answer 3

Induction therapy
Revert acute rejection episode
Long-term prevention

Risks/side effects

• infection
• malignancy
• side effects of steroids/cyclosporine

Question 4

Graft versus host disease - purpose of high dose therapy prior to HSCT, clinical features, prevention, treatment

Answer 4

MC cause of mortality in allogeneic HSCT

High dose therapy prior to HSCT for evacuating marrow, killing tumour cells, suppression host immunity

Clinical features: skin, liver, GI tract

Prevention: T cell inhibitor + cytotoxic

• but risk of graft rejection (donor T cells depleted)
• increased risk of cancer relapse

Treatment: steroid

Question 5

Organ transplant vs HSCT - graft, recipient, type of rejection

Answer 5

Organ
- immune innocuous graft
- immune-competent recipient
==> rejection of graft

HSCT
- immune aggressive graft
- immunocompromised recipient
==> rejection of recipient

Question 6

Immune surveillance - mechanism of cancer immunoediting, predictions in immune surveillance

Answer 6

Cancer immunoediting – selection of fittest mutants
- immune surveillance
+
- tumour cell mutation

Predictions of cancer/prognosis

• age
• immunocompromised
• TILs (increases OS, PFS and response to chemotherapy – tumour specific cytotoxic T cells recognise Ag peptides presented on MHC Class I of tumour cells)

Question 7

Tumour antigens - specific vs associated

Answer 7

Tumour specific
- e.g. viral Ag, mutated proteins a/w tumourigenesis

Tumour associated

• normal proteins expressed by cell lineages of normal cells
• aberrantly expressed normal proteins e.g. CEA, AFP, MAGE-1
• overly expressed normal proteins e.g. HER2

Question 8

Importance of identifying tumour antigens - markers, therapeutic Ab, CAR-T target, cancer vaccines

Answer 8

Tumour markers

• diagnosis
• monitoring
• localisation

Therapeutic Ab
- unconjugated and conjugated

CAR-T cell therapy
- extracellular Ab domain (specific to tumour surface Ag – doesn’t have to be on MHC!)
- intracellular T cell signalling domain (+ve proliferation into cytotoxic cells and release cytokine)
==> anti-CD19 therapy in B-ALL
- risk of fatal cytokine release syndrome

Cancer vaccines
- tumour Ag loaded onto immature dendritic cells and infused back to +ve anti-tumour immunity
(add differentiating cytokines, load Ag then add activating cytokines)
e.g. cancer testis Ag: MAGE-1; sipuleucel-T for advanced Ca prostate

Question 9

Immune evasion mechanisms and solutions

Answer 9

Low immunogenicity

• loss of MHC class I
• lack of expression of co-stimulatory CD80/86

==> cancer vaccines, interferon to +ve MHC I expression, IL-2 for T cell activation (but risk of infection and capillary leak syndrome)

Tumour-induced immunosuppression

• release TGF-beta and IL-10, release IDO (deplete tryptophan to cause T cell cycle arrest)
• induce Treg

==> ex-vivo activation of T and NK cells

• TILs (CTL) extracted from tumour –> add anti-CD3 and IL2 to stimulate T cells into mature CD8+ anti-tumour cells
• NK cells from peripheral blood –> add IL2 to simulate into lymphokine activated killer cells

Immune checkpoints

• PDL1 on tumour cells bind to PD1 to decrease EFFECTOR T cell
• CTLA4 bind to CD80/86 to decrease NAIVE T cell

==> CTLA4, PDL1 or PD1 inhibitors