L21-22: Tumour Immunity

Question 1

NK cells and tumours

Answer 1

Express stimulatory and inhibitory cell surface receptors:
STIMULATORY e.g. FcR, CD2, NKG2D
INHIBITORY - MHC-I binding receptors that prevent killing

Question 2

B Cells/Antibody tumour immunity

Answer 2

B cells can produce Ab against tumour antigens
Ab binds tumour antigen. Fc region of bound Ab recognised by FcR+ cells such as NK cells, macrophages
FcR ligation leads to cellular activation
ADCC (antibody dependent cellular cytotoxicity)
Antibody can also lead to Complement dependent tumour cell lysis

Question 3

T cell tumour immnity

Answer 3

Lone naive CD8 T cell stimulation through its TCR (no signal 2) leads to anergy.
DC can present exogenously derived Ag via MHC-I pathway and prime CD8 T cells “cross-priming”
DCs can also present to CD4 via MHC-II, which become helper T cells and further enhance CTL activation
End result is an effector CTL that can kill the tumour cell

Question 4

NKG2D function

Answer 4

NKG2D receptor expressed on NK cells allows recognition of stressed cells by NK cells that still express MHC-I.
Stressed cells upregulate MIC-A - a ligand for NKG2D receptor

Question 5

NKT cell TCR recognises

Answer 5

CD1d (MHC-I-like) plus glycolipid Ag

Question 6

NKT role and function

Answer 6

Very potent cytokine producers (IFNg, IL-4, TNF, provide help for NK and CTL, enhance DC activation

Question 7

Tumour escape mechanisms

Answer 7

Antigenic modulation:
Tumours genetically unstable - can lose Ag
Lose MHC-I alleles - if all are lost, may become NK cell targets; if some are lost may evade NK cell and CTL
Production of immunosuppressive factors:
TGF-beta, IL-10, PD-L1

Question 8

Anti-tumour therapy

Answer 8

preventative immunotherapy - virus vaccines
Ab-based immunotherapy - mAb generated against tumour Ag
Cytokine based immunotherapy

Question 9

Antibody-Based Immunotherapy Method and Challenges

Answer 9

mAb can be generated against tumour antigens
Can be injected to target, inhibit and kill tumours
Either alone or coupled to reagents that kill target.
mAb alone – block molecules important to tumour growth, or activates FcR+ cells (e.g. NK) to kill tumour
mAb-toxin conjugate (eg. Ricin) (Immunotoxin)
mAb-radioisotope conjugate
Challenges:
Specificity of Ab (binding to non-tumour cells)
Penetration into large tumours
Instability of tumours (escape mutants)
Limited knowledge of dominant tumour antigens
examples: Anti-CD20 (Rituximab)

Question 10

Cytokine based immunotherapy

Answer 10

IL-2, IFNa, TNF, IL-12
Problems: Limited success with some tumour types
Often toxic when used systemically
Short half life

Question 11

Immunisation with tumour cells or antigens

Answer 11

Patient immunised with killed tumour cells, or purified tumour antigens with adjuvant such as BCG, or tumour Ag pulsed onto patient’s DCs.
Problems:
Dominant tumour Ag may be underrepresented in whole tumour preps
Dominant tumour Ag may be patient specific – not widely applicable
MHC-restricted Ag presentation (eg. MAGE1 – only in HLA-A1 patients)
Antigenic modulation – outgrowth of escape mutants
Risk of autoimmunity due to other non-tumour Ag in prep
eg. Vitiligo –destruction of normal melanocytes

Question 12

Adoptive CAR T Cell Therapy

Answer 12

Chimeric Antigen Receptor T cells:
Patient T cells engineered to express modified tumour Ag-specific antibody receptors (eg. anti-CD19 B cell leukemia marker) fused to intracytoplasmic T cell stimulatory (signal 1) (eg. from CD3zeta) and costimulatory (signal 2) domains (eg. from CD28).
These cells are expanded in vitro and reintroduced to the patient.
Capable of potent tumour destruction.