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
What do they mediate their function through
Cytokines release
IL10
TGF-beta
Direct cell to cell contact
What are they important for
Controlling immune responses to self Ag
May play a role in tumour escape
May be selectively recruited to the tumour site by chemokines
What are myeloid derived suppressor cells
Heterogeneous population of cells of myeloid origin
Comprise of myeloid progenitor cells and immature macrophages, granulocytes, and DC
What do they do
They expand during cancer, inflammation, and infection
Potent suppressor of T cell function
Show upregulated expression of immune suppressive factors : Arginase 1 and iNOS
Both metabolise L- arginine shortage of l-arginine inhibit T cell function
INoS generate NO this inhibits T cell function and induces apoptosis
May induce t regs
T cell based therapies
Non specific T cell stimulation
Vaccination
Adoptive T cell therapy - TIL and CAR
What do you do in non- specific T cell stimulation
Give immunostimukatory cytokines IL12
This can be toxic - IL12 can cause vascular leak syndrome
also, block of immunologic checkpoints - antagonist Ab specific for CTLA4
Also PD ligand 1 and 2
What is CTLA4
CTLA4 is a coinhibitory that regulates the level of costimulation by binding to Cd80/86
In competition for costim CD 28
Mab are used to block this then T cell can be stimulated
Drug used is Ipilimumab
What is PDL1 and what does it do
Binds to PD 1 and inhibits the T cell
Block this the T cell can be activated
Drug used is Pembrolizumab
Vaccination - tumour cell lines
Currently being tested
Tumour cell lines must be irradiated or lysated to make them safe
May then enhance the immunogenicity of the tumour cells by stimulating cd80/86
Vaccination - defined peptides or protein Antigesn
These are purifies or expressed from recombinant viruses, DNA or RNA
They are peptides so are more immunogenic
Vaccination - dendritic cell based vaccines
Sipuleucel-T (Provenge) used to treat metastatic prostrate cancer
DCs are given alongside prostatic acid phosphatase and GM-CSF
Helps to elicit a better immune response by directly stimulating T cells
Adoptive T cell therapy works by infusing
Whole T cell population - donor lymphocyte infusion CML patients who relapse after allogenic BMT
Infusing selected, tumour specific T cells
Infuse selected, tumour specific T cells - what happens
Select t lymphocytes from the patient
Find tumour specific lymphocytes
Expand the specific T cell in vitro to make a large population - activate more effectively in vitro so get a high frequency of T cell that will respond
Infuse patients own T cells back in - reduced risk of graft vs host disease
V expensive nontoxic widely available,
Support development of vaccination strategies
Tumour infiltrating lymphocytes therapy type of infusion
Biopsy the tumour - identify tumour infiltrating lymphocytes
Select tumour specific TIL
Expand
Infuse them with IL 2
Patient is treated with chemotherapy- dose of non myeloblative conditioning + cyclophosphamide and fludarabine to deplete the own immune system so the incision has more chance of working
Also deplete any t regs
Chimeric Ag receptors
Combing the specificity of a mab with the killing ability of a T cell
BCR taken from a B cell that is specific to the tumour
Can be from the patient or a healthy donor
This receptor is put onto a T cell
T cell is now a hybrid and has better killing ability
Benefits of CARs
Transferral of the receptor onto the patients own T cells means that there is no risk of graft vs host disease
Faster method of generic engineering on,y needs 4-5 days
What does conditioning patients with chemotherapy before T cell infusion do
Can increase homeostatic proliferation in these cells
Can eliminate host t regs
What does radiotherapy do
Might improve Ag processing/presentation. In tumour cells
What are the potential SE of T cell infusion
Autoimmunity
Cause a response to own cells
TIL therapy resulted in symptoms of autoimmune melanocytes destruction in some melanoma patients
Same with blocking CTLA4 or PD1 can cause autoimmune responses cannot chose which CTLA4 to inhibit
SE enhancement of tumour growth by e immune system
Targeting and activating the immune system cause inflammatiom and chronic inflammation has been associated with increased risk of tumour progression
Enhance angiogenesis and tumour remodelling
Promote protein and DNA damage through oxidative stress
Polarise immunity towards tumour promoting phenotype
Use of monoclonal Ab for cancer therapy what are there mechanisms of action
Complement mediated lysis - Ab binds to CD 20
Causes activation of the complement cascade
Leads to develops MAC
ADCC - Ab binds to CD20
Fc- gamma receptor on NK cells binds to the antibody - tumour cell killed by NK cell
Examples of Mab
Rituximab - antiCD20
Trastuzumab - ant HER2
Bevacizumab- and VEGF
Direct effects - blocking receptor ligand interactions
Ipilimumab binds to CTLA4 directly blocking the immune checkpoint
Herceptin inhibits ligands blocking proliferation
Direct effects antiangiogeneis
Avastin directed against VEGF
Blocks its interaction with receptors
Only works in combination with cytotoxic drugs and normalises vasculature
Direct effects - cytotoxic activity of conjugated Ab
Ab bound to radionuclide
Radiation reaching target cell induces DNA damage and apoptosis
Ab bound to protein toxin molecule
Ab bound to cytotoxic drug
