Tumour Immunology Flashcards
Aetiology of CA
Transformation of germline cells.
Transformation of somatic cells.
Environmental factors.
Hallmarks of CA
Growth self-sufficiency
Evade apoptosis
Ignore anti-proliferative signals
Limitless replication potential
Sustained angiogenesis
Invade tissues
Escape immune surveillance
The immune system discriminate what from what?
Self from non-self based on molecules expressed on the cell surface.
What is the ultimate goal of tumour immunology?
Induce clinically effective anti-tumour immune responses that would discriminate between tumour cells and normal cells in CA patients.
What do we call it when the immune system work against us?
Autoimmune disorder. (Also supports CA sometimes).
True or false?
The immune system is capable of early recognition and elimination of CA cells in the process of malignant transformation.
True
What components of the immune system play a part in killing cancer cells?
T-cells, NKT cells, NK cells
Cancer immunosurveillance
Immune system can recognise and destroy nascent transformed cells, normal control
Cancer immunoediting
Tumours tend to be genetically unstable -> immune system can kill and induce changes in the tumour resulting in tumour escape and recurrence.
What does the surveillance theory propose?
Lymphocytes acted as sentinels - mopping up newly arising tumours.
Tumour antigens have (how many groups)?
Two: tumour specific antigens, tumour associated antigens.
Tumour specific antigens TSA
Only found on tumours.
Result of point mutation or gene rearrangement.
Derive from viral antigens.
Tumour associated antigens TAA
Found on both normal and tumour cells - overexpressed in CA cells.
Developmental antigens which become depressed (CEA).
Differentiation antigens are specific.
Altered modification of a protein could be an antigen.
Lab experiment - proof of tumour antigen
Mice example.
Tumour antigens classification
Tumour specific mutated oncogone or tumour suppressor gene.
Germ cell. (MAGE1, MAGE3, normal testicular proteins, but found in melanoma, breast, glioma)
Differentiation.
Abnormal gene expression.
Abnormal post translational modification.
Abnormal post transcriptional modification.
Oncoviral protein.
Evidence for human tumour immunity
Spontaneous regression: melanoma lymphoma.
Regression of metastases after removal of primary tumour: pulmonary metastases from renal carcinoma.
Infiltration of tumours by lymphocytes and macrophages: melanoma and breast CA
Lymphocyte proliferation in draining lymph nodes.
Higher incidence of CA after immunosuppression, immunodeficiency, aging…
Tumour escape
Immune responses change tumours such that tumours will no longer be seen by the immune system.
Immune evasion
Tumours change the immune responses by promoting immune suppressor cells.
Low immunogenicity
No peptide:MHC ligand, no adhesion molecules, no co-stimulatory molecules.
How tumours treated as self-antigens lead to tolerisation by T-cells?
Tumour AGs taken up and presented by APCs in absence of co-stimulation tolerise T cells.
Antigenic modulation
AB against tumour cell-surface AG can induce endocytosis and degradation of the AG. Immune selection of AG-loss variants.
Tumour-induced immune suppression
Factors (TGF-beta) secreted by tumour cells inhibit T cells directly. Induction of regulatory T cell by tumours.
Tumour-induced privileged site
Factors secreted by tumour cells create a physical barrier to the immune system.
Immunotherapy
Learn how to harness the immune system to kill tumours.
Induce immune response against tumour that would discriminate between tumour and normal cells. (adaptive immunity)
Immunotherapy can be
Active: vaccination (killed tumour vaccine, purified tumour AGs, Professional APC-based vaccines, Cytokine- and co-stimulator-enhanced vaccines, DNA vaccines, viral vectors).
Passive: adoptive cellular therapy (T cells)
Anti-tumour Antibodies (HER2, CA-125).
Cell-based therapy…
Activate patient’s immune system to attack CA.
Deliver vehicle to target therapeutic genes to attack tumours.
Do not act directly on CA cells - work systematically to activate the body’s immune system.
Dendritic cells
Found throughout the body
Interstitial cells - Langerhans cells of the epidermis.
Detect and chew up foreign invaders -> present proteins on their surface.
What needs to be done to make a DC vaccine?
Collect blood of CA PT -> enrich to increase the DC population.
Describe the process of making DC cells
Leukapheresis -> monocytes -> 6 day culture in GM-CSF/IL-4 -> become immature DCs -> exposed to autologous tumour extracts, whole tumour mRNA, viral vectors, synthetic peptides, allogenic tumour extract (activating molecules) -> activated APC back to circulation.
T cells - how to make them?
Tumour biopsy -> Isolation of tumour fragments -> cultivation of TILs propagated on tumour fragments -> expansion and infusion back into the body.
Macrophages
Blood - monocyte - macrophage - therapeutic macrophage - tumour - therapeutic effect.
Tumour hypoxia
Hypoxia (low oxygen) is a prominent feature of malignant tumours
Inability of the blood supply to keep up with growing tumour cells
Hypoxic tumour cells adapt to low oxygen
What are the problems with tumour hypoxia?
Tumour hypoxia = poor patient prognosis
Stimulates new vessel growth
Suppresses immune system
Resistant to radio- and chemotherapy (repopulate the tumour)
Increased tumour hypoxia after therapy
