Tumour Biology: Focus on Tumour Immunology

Question 1

What Concept was first proposed by MacFarlane Burnet in the 1950s? Describe it.

Answer 1

Immunosureillance

the physiological function of the immunosystem to recognise and destroy clones of transformed cells before they grow into tumours.

Question 2

What are the three ways a premalignant tumour can progress in the human body?

Answer 2

1. escape = forms a primary tumour then metastisis
2. equilibrium = remains a premalignant tumour
3. elimination = returns to normal tissue

Question 3

What are the 3 key concepts in tumour immunity?

Answer 3

1. Tumours express antigens that are recognised as foreign by the host immune system
2. immune responses frequently fail to prevent the growth of tumours
3. Immune system can be activated by external stimuli to effectively kill tumour cells and eradicate tumours

Question 4

What mononuclear cells surround a tumour?

Answer 4

T lymphocytes

NK cells

Macrophages

Question 5

When there is the presence of infiltrations of lymphocytic cells in tumours. Is this a good or bad prognosis?

Answer 5

Good, as there are cells which are fighting the tumour and show that the tumour is not completely invisible to host

Question 6

What types of cells are associated with a positive association in immunocontexture?

Answer 6

Cytotoxic T Lymphocytes (CD3+CD8+ cells)

Memory T cells

Question 7

What locations are positively associated in immune contexture?

Answer 7

If the CTLs and memory T cells are located in the core of the tumour or the invasive margin of the tumour

Question 8

How do cytotoxic T cells influence the immune response towards tumours?

Answer 8

Is the principle mechanism in which adaptive immune system

works in conjunction with CTLs

kill cells which present MHC class I but when the antigen presented is recognised as NOT self

Question 9

How do NK cells kill tumours?

Answer 9

NK cells kill cells that have reduced MHC class I presentation

respond to the absence of MHC class I as recognition of MHC class I inhibits NK cells

Question 10

What specific ligands do tumours present which activate NK cells? and What receptor will they activate?

Answer 10

MIC-A

MIC-B

ULB

All activate NKG2D receptors on NK cells

Question 11

How are activated by the adaptive immune system (hint Ig)

Answer 11

IgG antibody-coated tumour cells by binding to the Fc receptors (FcεRIII or CD16).

Question 12

What factors increase the tumoricidal capacity of NK cells?

Answer 12

cytokines

Interferon-γ

IL-15 and IL-12

Question 13

What stimulates NK cells to become LAK cells?

Answer 13

IL-2 activates NK cells to become Lymphokine-Activated Killer Cells (LAK)

Question 14

What are the two different types of Macrophages?

Answer 14

Macrophage Class 1

Macrophage Class 2

Question 15

What is the difference between macrophage classes?

Answer 15

Macrophage Class 1

• when activated will kill tumour cells
• good Immunoscore
• tumours possible activate it by = recognition of damage-associated molecular pattern from dying tumour cells by Macrophage TLRs
• use phagocytosis to kill tumours
• production of NO is prominent & can kill tumours in vivo

Macrophage Class 2 (phenotype)

• secrete VEGF
• Transforming Growth Factor Beta
• • other soluble factors
• causes further angiogenesis of the tumour

Question 16

What are the different types of tumour antigen classes? What specific Antigens do they possess?

Answer 16

Tumour Specific Mutated Oncogene or Tumour suppressor

• Cyclin-dependant kinase 4 = Cell-cycle regulator (Melanoma)
• B-Catenin = relay signal transduction pathway (melanoma)
• Capsase-8 = regulator of apoptosis (Squamous cell carcinoma)

Germ Cell

• MAGE-1 & MAGE-2 = normal testiculat proteins (melanoma, breast, glioma)

Question 17

What are some sources of peptide antigens in mutated tumour antigens?

Answer 17

• MART 2
  
  • Disease = Melanoma
  • HLA restriction = A1
• ME1
  
  • Disease = non-small cell lung carcinoma
  • HLA restriction = A2
• p53
  
  • Disease = Head and Neck squamous cell carcinoma
  • HLA restriction = A2

Question 18

What is the difference between high and low tumour antigenicity?

Answer 18

• High tumour antigenicity = proinflammatory response
  
  • if they tumour has a number of antigens derived form dif proteins
  • and is recognised as non-self
  • slower tumour growth
  • or tumour regression
• Low tumour antigenicity = counter-regulatory immune response
  
  • bad immunoscore
  • is a worse prognosis
  • causes tumour progression

Question 19

What are the two major types of antigens that are recognised by endogenous T cell responses?

Answer 19

tumour associated antigens

tumour specific antigens

Question 20

What mechanism allows individual tumour cells to escape recognition?

Answer 20

intratumoral heterogeneity

holes in the TCR repertoire and T cell tolerisation and exhaustion can limit response

Question 21

What effect to myeloid derived cells have on the immune response?

Answer 21

suppresses Ag-specific T cell activation

Supresses CD3/CD28 activation

if you suppress antigens & you inhibit it = inhibition of the immune reponse

Question 22

What specific immune and nonimmune mechanisms do Myeloid derived stem cells use to promote tumour progression?

Answer 22

increase angiogensis

increase M2 phenotypic macrophages

increase T regulator cells

reduce NK cells

reduce T cell activation

increase cancer cell stemness

decrease blood glucose

Question 23

How do tumour cells evade the immune response?

Answer 23

1. many tumours have specialised mechanisms for evading host immune responses
2. tumour cells are derived from host cells and resemble norm cells in many respects

• tend to be WEAKLY IMMUNOGENIC
• elicit strong immune responses induced by oncogenic viruses
• spontaneous tumour induce weak immunity

3. the rapid growth and spread of a tumour may overwhelm the capacity of the immune system to effectively control the tumour

Question 24

How do tumours ACTIVELY inhibit immune responses?

Answer 24

inhibition of T cell responses via CTLA-4 or PD-1.

role of CTLA-4 is that tumour antigens are presented by APCs

low levels of B7 costimulates may be enough to engage the high-affinity receptor CTLA-4

Question 25

What secreted products of tumour cells may suppress anti-tumour immune responses?

Answer 25

an example of immunosuppressive tumour product is TGF-beta

is secreted in large quantities

inhibits proliferation and effector functions of lymphocytes and macrophages

Question 26

How to regT cells suppress T cell responses to tumours?

Answer 26

increased number of reg T cells are increased in tumour-bearing individuals

these cells can be found in the cellular infiltrates in certain tumours

depletion of regulatory T cells in tumour-bearing mice enhances anti-tumour immunity and reduces tumour growth

Question 27

How do tumour-associated macrophages promote tumour growth

Answer 27

M2 phenotype macrophages

secreted mediators such as IL-10, and prostaglandin E2

impairs T cell activation and effector functions

Conversely, tumour-association macrophages also secrete factors that promote angiogenesis (i.e. TGF-beta, VEGF)

Question 29

What are the 5 types of immunotherapy of tumours?

Answer 29

1. Cytotoxic T cell targeting (e.g. bispecific antibodies)
   * Brings host T cell and tumour cell together
2. Adoptive transfer of ex vivo expanded autologous tumour-reactive T cells
   * increase efficiency, increase boosting activity, increase the number of it
3. Alloreactivity
4. Tumour Cell Vaccine
   * tumour introduce vaccine
5. Host DC vaccination

Question 30

What is Adoptive Immunity?

Answer 30

Lymphocyte isolated from the blood or tumour infiltrate of a patient may be expanded by culture in IL-2 and infuse back into the patient

Question 31

What are Car T cells?

Answer 31

Chimeric antigen receptor T cells therapy

treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse