Tumour Immunology Flashcards
What does taking tumour cells from a mouse irradiating the cells vaccinating a mouse with them and then challenging the vaccinated mouse with live tumour cells -> mouse develops no tumour
Show?
Tumours can induce an immune response
What does surgically resecting a mouse tumour culture the cells challenge original mouse - mouse remains tumour free show?
Tumours can induce immunological memory
What cells are suggested to play a key role as without them no immune response is seen
T cells
What is the evidence of tumour protective immunity in humans?
Immunosuppressed individuals more frequently develop cancer than immunocompetent individuals - no immune system to respond
Cancer patients can develop spontaneous immune responses to their own tumours - rare sometimes people can cure their cancer this way
The presence of immune cells within some tumours correlates with improved prognosis
What is cancer immunosurveillance
It predicts that the immune system can recognise precursors of cancer
In most cases these precursors are destroyed before they e come clinically apparent
Immunosuppressed mice indicate this theory as correct
What is cancer immunoeditting
Immune system editing the tumour that eventually forms - what sort of tumour it becomes
What are the 3 Es of immunoediting
Elimination- immune mediated destruction of most cancer cells
Equilibrium- dynamic equilibrium between the cancer cell variant and the immune system that has survived the elimination phase
Immune system contains but cannot illuminate the cells
As they are mutating unstable cells - a certain mutation will give them an advantage
Escape- mutation with the advantage has arisen and can now grow out in an immunologically intact environment - when they become clinically apparent
How do T cells interact and destroy cancer? How are T cells activated ?
2 independent signal are needed
1) TCR MHC interaction
2) CD28 - CD80/86 interaction
Any foreign antigen presented on cells via MHC1 can activate the dendritic cells who present MHC1 and 2 activate the T cells
Tumour associated antigens - what do the cells look like to make them noticeable as foreign to the immune system
Mutated self proteins - from DNA damage, CDK cell cycle regulators, beta catenin,
Aberrantly or over expressed proteins - oncofoetal antigens that are normally expressed in embryogenesis - AFP
Lineage specific (differentiation) antigens - only expressed in certain cell lineages
Abnormal post translational modification of self protein MUC1 mucin normally heavily glycosylated but in under glycosylated in breast and la creator cancer and is recognised as abnormal
Viral proteins - these are foreign proteins HPV in cervical cancer, EBV in Hogkins lymphoma
Also
Tumour stroma can be targeted may be different to normal so detected as foreign
What makes a good target antigen?
Tumour specific - this will reduce toxicity to the rest of the body, making the drug more efficient
Antigen is shared amongst patients with same and different tumour types - treatment can be widely used more cost effective
Antigen must be critical for tumour survival and growth - if essential all tumour cells will express it if not only a certain percentage of cell can be targeted so it will come back more advantageous than before
Lack of immunological tolerance - most T cells are tolerant to their own cells, most Ag in cancer are their own Ag therefore will elicit no T cell response, Ag needs to be different enough from own cells to generate an immune response from high acidity T cells
What is central tolerance
The mechanism by which newly developing lymphocytes are rendered tolerant to self, it occurs in the thymus
What is peripheral tolerance
Immunological tolerance developed after T and B cells mature and enter the periphery. This includes the suppression of autoreactive cells by Tregs and the generation of hyporesponsiveness - anergy in lymphocytes which encounter Ag in the absence of costimulatory signals required for T cell response
Mechanisms tumours use to escape immune response
Loss of MHC 1 expression
Reducted expression of other molecules in antigen processing /presentation
Loss of costimulatory molecules -CD80/86 causing anergy
Loss of adhesion molecules stops T cell stabilising with cancer cell my prevent T cell exiting vasculature
Loss of target Ag - no Ag to present - loss of variant cells
Protection from lysis - questioned - block direct killing by locking granzyme perforin pathway - blocks direct killing
Inhibiting T cell infiltration - endothelium b receptor expression on tumour endothelium, prevents modulation of ICAM reduces T cell adhesion to vasculature, nitrosylation of chemokines can stop them acting as chemoattractants - T cell cannot enter tumour
There can be immunosuppression at the tumour site
TGF- beta
Suppresses anti tumour T cell interaction and induces t regs
IDO - indoleamine 2,3 dioxygenase
Expressed by tumours that catabolise tryptophan
Can block cd8 T cell proliferation
Promotes apoptosis of cd4 T cells
Factors that inhibit differentiation maturation and function of local DCs so they cannot present Ag and treg differentiation is promoted
What are t reg cells
Inhibit an immune response by influencing the activity of another cell type
What are treg markers
CD4, foxp3, cd25, Cd127
