W12L19 - Tumour Immunology

Question 1

Key Concepts in Tumor Immunity

Answer 1

1. Tumors express Ags that are recognised as foreign by host immune system
2. Immune responses frequently fail to prevent the growth of tumors
3. Immune system can be activated by external stimuli to kill tumor cells

Question 2

What are most tumors surrounded by?

Answer 2

Mononuclear cell infiltrates 
Composed of:
- T lymphocytes
- NK cells
- macrophages
Activated lymphocytes and macrophages are present in lymph nodes draining the sites of tumor growth

Question 3

CD8 Cytotoxic T Cells

Answer 3

Principal mechanism of adaptive immune response protection against tumors
CTLs perform surveillance function by recognising and killing potentially malignant cells that express peptides derived from tumor antigens
These then presented in association with class 1 MHC
Mononuclear cells derived from inflammatory infiltrate in human solid tumors contain CTLs with capacity to kill tumor from where derived
The inability to detect tumor specific CTLs in some patients is because of regulatory mechanism of the tumor
Blocking these inhibitory pathways leads to development of strong T cell responses against the tumor

Question 4

NK Cells

Answer 4

Kill may types of tumor cells, especially that have reduced class 1 MHC expression and express ligands for NK cell-activating receptors
Also respond to absence of class 1 MHC because the recognition of class 1 MHC molecules delivers inhibitory signals to NK cells

Question 5

What are Lymphokine-Activated Killer Cells

Answer 5

IL-2 activated NK cells
Derived by culture of peripeheral blood cells or tumor-infiltrating lymphocytes from tumor patients with high does of IL-2
More potent killers of tumors than unactivated NK cells

Question 6

Macrophages

Answer 6

Capable of both inhibiting and promoting growth and spread of cancers, depending on activation state
M1 macrophages can kill tumor cells by mechanisms they use to kill infectious organisms
M2 macrophages contribute to tumor progression by secreting vascular endothelial growth factor and transforming growth factor-B

Question 7

High and Low Tumor Immunogenicity

Answer 7

High - proinflammatory responses dominate

Low - counter-regulatory responses dominate

Question 8

What does cancer cell activity lead to in cells?

Answer 8

Altered nutrient availability
Presence of immunosuppressive signals
Relative hypoxia
Waste accumulation within the TME (tumor microenvironment)

Question 9

Myeloid-Derived Suppressor Cells

Answer 9

Halt immune response vs cancer
Use immune and nonimmune mechanisms to promote tumor progression but have beneficial effect in other settings
They:
- inhibit adaptive antitumor immunity by suppressing CD4 and CD8 T cell activation and function
- inhibit innate immunity by polarising macrophages toward type-2 tumor promoting phenotype
- promote cancer stemness, facilitate angiogenesis and drive tumor invasion and metastasis

Question 10

Beneficial effects of MDSCs

Answer 10

Lowering of blood glucose
Reduction of insulin tolerance in obese people
Maintenance of maternal fetal tolerance and embryo implantation during pregnancy

Question 11

Evasion of Immune Response by Tumors

Answer 11

Failure to produce tumor antigen - lack of T cells recognition of tumor
Mutations in MHC genes needed for antigen processing - lack of T cell recognition of tumor
Secretion of immunosuppressive proteins or expression of inhibitory cell surface proteins
Tumor cells similar to host cells making them weakly immunogenic
Rapid growth and spread can overwhelm immune system

Question 12

Active Inhibition of Immune Responses

Answer 12

Tumors engage inhibitory mechanisms to suppress immune responses
T cell responses are inhibited by CTLA-4 or PD-1
Secreted products of tumor cells suppress anti-tumor immune responses
- TGF-B which is secreted in large numbers by tumors inhibits proliferation and effector functions of lymphocytes and macrophages
Regulatory T cells may suppress T cell responses to tumors

Question 13

CTLA-4 and PD-1

Answer 13

CTLA-4
- tumor antigens presented by APCs in absence of strong innate immunity and thus with low levels of B7 costimulators
- these low levels are enough to engage high affinity receptor CTLA-4
PD-1
- PD-L1 is a ligand for T cell inhibitory receptor PD-1 is expressed on many human tumors
- anti-tumor T cell responses are compromised by PD-L1 expression

Question 14

Adoptive Cell Therapy

Answer 14

Lymphocytes isolated from the blood or tumor infiltrate of a patient may be expanded by culture in IL-2 and infused back into patient
Lymphocytes may be transfected with chimeric antigen receptor (CAR) genes
This treatment combined with systemic IL-2 administration leads to tumor regression or T cells may genetically tranduce into CARs

Question 15

CARs

Answer 15

Chimeric antigen receptors
Composed of receptor domains specific for tumor antigens and signalling domains
- ITAMs
- cytosolic motifs of CD28 which promotes robust T cell activation
Consists of a bottom endodomain and top ectodomain
Ectodomain contains, spacer, linker and signal

Question 16

Adoptive Cell Therapy with CAR-modified T cells

Answer 16

T cells selected from blood
T cell activation and gene transfer
Expansion (making loads more)
Lympho-depletion and infusion with CAR T cells