Tumour Biology: Focus on Tumour Immunology Flashcards
What Concept was first proposed by MacFarlane Burnet in the 1950s? Describe it.
Immunosureillance
the physiological function of the immunosystem to recognise and destroy clones of transformed cells before they grow into tumours.
What are the three ways a premalignant tumour can progress in the human body?
- escape = forms a primary tumour then metastisis
- equilibrium = remains a premalignant tumour
- elimination = returns to normal tissue
What are the 3 key concepts in tumour immunity?
- Tumours express antigens that are recognised as foreign by the host immune system
- immune responses frequently fail to prevent the growth of tumours
- Immune system can be activated by external stimuli to effectively kill tumour cells and eradicate tumours
What mononuclear cells surround a tumour?
T lymphocytes
NK cells
Macrophages
When there is the presence of infiltrations of lymphocytic cells in tumours. Is this a good or bad prognosis?
Good, as there are cells which are fighting the tumour and show that the tumour is not completely invisible to host
What types of cells are associated with a positive association in immunocontexture?
Cytotoxic T Lymphocytes (CD3+CD8+ cells)
Memory T cells
What locations are positively associated in immune contexture?
If the CTLs and memory T cells are located in the core of the tumour or the invasive margin of the tumour
How do cytotoxic T cells influence the immune response towards tumours?
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
How do NK cells kill tumours?
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
What specific ligands do tumours present which activate NK cells? and What receptor will they activate?
MIC-A
MIC-B
ULB
All activate NKG2D receptors on NK cells
How are activated by the adaptive immune system (hint Ig)
IgG antibody-coated tumour cells by binding to the Fc receptors (FcεRIII or CD16).
What factors increase the tumoricidal capacity of NK cells?
cytokines
Interferon-γ
IL-15 and IL-12
What stimulates NK cells to become LAK cells?
IL-2 activates NK cells to become Lymphokine-Activated Killer Cells (LAK)
What are the two different types of Macrophages?
Macrophage Class 1
Macrophage Class 2
What is the difference between macrophage classes?
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
What are the different types of tumour antigen classes? What specific Antigens do they possess?
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)
What are some sources of peptide antigens in mutated tumour antigens?
- 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
What is the difference between high and low tumour antigenicity?
- 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
What are the two major types of antigens that are recognised by endogenous T cell responses?
tumour associated antigens
tumour specific antigens
What mechanism allows individual tumour cells to escape recognition?
intratumoral heterogeneity
holes in the TCR repertoire and T cell tolerisation and exhaustion can limit response
What effect to myeloid derived cells have on the immune response?
suppresses Ag-specific T cell activation
Supresses CD3/CD28 activation
if you suppress antigens & you inhibit it = inhibition of the immune reponse
What specific immune and nonimmune mechanisms do Myeloid derived stem cells use to promote tumour progression?
increase angiogensis
increase M2 phenotypic macrophages
increase T regulator cells
reduce NK cells
reduce T cell activation
increase cancer cell stemness
decrease blood glucose
How do tumour cells evade the immune response?
- many tumours have specialised mechanisms for evading host immune responses
- 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
- the rapid growth and spread of a tumour may overwhelm the capacity of the immune system to effectively control the tumour
How do tumours ACTIVELY inhibit immune responses?
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
What secreted products of tumour cells may suppress anti-tumour immune responses?
an example of immunosuppressive tumour product is TGF-beta
is secreted in large quantities
inhibits proliferation and effector functions of lymphocytes and macrophages
How to regT cells suppress T cell responses to tumours?
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
How do tumour-associated macrophages promote tumour growth
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)
What are the 5 types of immunotherapy of tumours?
- Cytotoxic T cell targeting (e.g. bispecific antibodies)
* Brings host T cell and tumour cell together - Adoptive transfer of ex vivo expanded autologous tumour-reactive T cells
* increase efficiency, increase boosting activity, increase the number of it - Alloreactivity
- Tumour Cell Vaccine
* tumour introduce vaccine - Host DC vaccination
What is Adoptive Immunity?
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
What are Car T cells?
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
