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Flashcards in Tumour Immunology Deck (16)
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1
Q

Types of TAAs

A

Mutated self proteins
Aberrantly/overexpressed self proteins
Lineage specific antigens e.g. Mart1/Melan A in melanoma
Abnormal post translational modification of self protein e.g. over/under glycosylation
Viral proteins - foreign
Tumour stroma + microenvironment

2
Q

What makes a good target for tumour immunotherapy.?

A

Tumour specific e.g. mutated self proteins
Shared amongst same + diff cancers e.g p53 mutation
Critical for tumour growth + survival
Lack of immunological tolerance so T cells can react

Lineage specific antigens are usually not good

3
Q

Molecules that aid adhesion of T cell to APC

A

ICAM (binds to T cell LFA)
ICAM-3 on T CELL
CD2/LFA-3

4
Q

How can tumours escape immune response?

A
  • loss of MCH i expression
  • reduced expression of other molecules involved in antigen processing e.g. TAP1 in colorectal cancer
  • loss of costimulatory molecule expression (CD80/86)
  • loss of target antigen
  • overexpression if enzyme inhibitors to prevent performing-granzyme mediated lysis
  • inhibit T cell infiltration
5
Q

How do tumours inhibit T cell infiltration?

A

Endothelial B receptor on tumour signals to prevent modulation of ICAM recusing adhesion of T cell to tumour vasculature

Nitrosylation of chemokines keep T cells from entering tumour core

6
Q

How many immunosuppressive occur at the tumour site?

A

TGF-b produced by tumour suppresses T cells + induces Treg
IDO expressed by tumours block CD8 cell proliferation + promotes apoptosis of CD4 + induces T Reg
Secretion of local factors that inhibit DCs e.g. VEGF, IL-6, IL-10, TGF-b
Expression of FAS-L by tumour can cause death of CD95 (FAS) expressing Tcells

7
Q

What are MDSCs?

A

cells of myeloid origin (progenitor + immature cells)
expand during cancer, inflammation + infection
suppress t cell function by up-regulating factors such as arginine 1, iNOS
- these metabolise L-arginine which is required for T cell function
iNOS generates NO that induces T cell apoptosis & induce Treg

8
Q

Types of T cell, based therapy for cancer?

A

Non specific T cell stimulation (checkpoint blockade?)
Vaccination
Adoptive T cell therapy

9
Q

Types of non specific T cell stimulation

A

Immunostimulatory cytokines e.g. IL2 - toxic results —> vascular leak syndrome
Immune checkpoint blockade

10
Q

Types of tumour vaccination

A

Tumour cells/lines (irradiated)- successful but poor. immunogenicity, lack of costimulation?
Defined tumour specific peptides - purified/expressed from recombinant viruses
DC based - pre load DCs w tumour proteins + insect back into patient

11
Q

Types of adoptive T cell therapy

A

Infuse whole T cell population - risk of gvhd
Infuse tumour specific T cells (TIL therapy)
- T cells activated in vitro to be tumour specific to achieve high conc of activated cells in vivo (no gvhd)
- T cells taken form patient the self or donor
Can be combined w vaccination
Genetic engineering of T cells to make in tumour specific

12
Q

Problem with TIL therapy?

A

Difficult to select tumour specific lymphocytes (they all look the same)

13
Q

What are chimeric antigen receptors?

A

Fusion between TCR and antibody - MHC unrestricted & highly potent
Target any surface molecules not just epitopes (unlike TCR)
Works well for CLL & ALL

14
Q

Drawback of using chimeric antigen receptors?

A
Cytokine storm (too much signalling)
T cells may target other cells e.g. those expressing HER2
15
Q

Side effects of immune therapy?

A

iRAEs related to CTLA-4 blockade
Evidence of tumour enhancement due to increased inflammatory cytokines —> angiogenesis, tissue remodelling, DNA damage etc.
Autoimmunity esp w blockade & TIL therapy
- TIL —> autoimmune melanocyte destruction as it targets antigens all over body, not just tumour (vitiligo, uveitis)
Autoimmunity can be treated w steroids

16
Q

How can monoclonal antibodies be used in cancer therapy?

A
  • complement mediated lysis of cancer cell due to binding of Ab into antigen on cell
  • ADCC - recruitment of NK cell & ‘killing via perforins & granzymes (e.g. Rituximab)
  • majority block receptor- ligand interactions e.g. ipilimumab
  • anti-angiogenesis (blocking VEGF-receptor interaction)
  • cytotoxic action of conjugated antibodies (must be highly specific)