Tumour Immunology Flashcards
Why is there a failure to develop an anti-tumour immune response?
There can be development of anergy or DC inactivation which could be a result of a lack of costimulatory molecules, turmour induced deviation from TH1 (effector cell) response to a TH2 response Tumour cell MHC class 1 expression and down regulation which may be due to total allelic loss of MHC class 1 heavy chain, beta 2 microglobulin deletions, rearrangements or mutations, TAP mutations, or dysregulation from methylation/acetylation paaterns, transcriptional down regulation or deficient IFN-gamma signal transduction
What are the tumour-host immunological interactions?
Cancer cells may paralyze infiltrating CTLs and NK cells through the secretion of TGFbeta or other immunosuppressive factors
Regulatory T cells and myeloid derived suppressor cells can both suppress the actions of cytotoxic lymphocytes
What is the evidence immunoediting occurs in cancer?
Transplantation experiments have shown that cancer cells that originally arose in immunodeficient mice are often inefficient at initiating secondary tumours in synergic immunocompetent hosts
While tumours which arose in immunocompetent mice are equally effective at causing cancer in both types of hosts
This shows that tumours must undergo selection for immune evasive clones before tumours can develop
What is the evidence for the existence of tumour infiltrating lymphocytes?
Clinical epidemiology increasingly supports the existence of antitumoral immune responses in some forms of human cancer
Some patients with colon and ovarian tumours that are heavily infiltrated with CTLs and NK cells have a better prognosis than those that lack them, it is suggestive that this is also true of other tumours but the data is not yet as compelling
Some immunosuppressed organ transplantation recipients have been observed to develop donor-derived cancers suggesting that in the ostensibly tumour free donors the cancer cells had been held in check by the immune system
When can T cells be bad for cancer patients?
CD4+CDR+FOXP3+ Treg cells suppress tumour specific T cell immunity in ovarian cancer, contribute to tumour growth and accumulate during progression
Increased rations of Treg cells are associated with a high death hazard ratio and reduced survival
Treg cells preferentially moved to an accumulated in tumours and ascites but rarely entered draining lymph nodes in later cancer stages
Tumour cells and surrounding macrophages produced the chemokine CCL22 whih mediates the trafficking of Treg cells via CCR4
This specific recruitment of Treg cells might represent a mechanism by which tumours may foster immune privilege
What cytokines secreted by NK cells may play a role in cancer>?
They secrete IFNgamma, TNF, GM-CSF and others
IFNgamma stimulates up regulation of MHC 1 and 2 molecules which in turn enhances antigen presentation to the adaptive immune system
IFNgamma activates CTLs and Th cell responses
IFNgamma also blocks angiogenesis which can restrict tumour growth
Why are some cancers susceptible to NK?
NK cells discriminate between normal host and infectious organism by recognizing MHC 1 through an inhibitory receptors called killer inhibitory receptors which blocks NK cell killing if the cell binds to another cell with the same MHC 1 molecules then their cytotoxic and cytokine functions are blocked
this is termed HLA restriction
some tumours down regulate MHC to avoid CTL killing making them susceptible to NK cell killing
What does Galectin-1 on reed-sternberg cells do in hodgkins lymphoma?
Gal-1 is a lectin that binds 1,4 carbohydrate on T cell
Gal-1 induces TH2 cytokine production and regulatory T cells
This is likely a potent mechanism through which the R-S cell avoids immune attack and may make it a good therapeutic target
What are the 3 steps to effective cancer dendritic cell vaccines?
These optimally represent relevant tumour antigens there are then manipulations to immune regulation facilitating the CTL response this prevents CTL neutralisation at the site of the tumour
What ways can there be non-specific upregulation of the immune response to cancer?
IL-2
This was the only immunotherapy for many years, it causes T cell activation and proliferation but is very toxic causing high fevers and capillary leak
BCG-live attenuated vaccine, this would upregulated macrophage activity this is an old therapy that is still sometimes used in bladder cancer
What are the immunotherapies of lymohomas?
There are passive therapies where there is administration of antibodies, T cells of NK cells to the patient as well as active therapies such as vaccination or regulatory blockades
What is the anti-tumour activity of Brentuximab vedotin?
This is a monoclonal antibody which binds to CD30 and is trafficked to the lysosome it is the monomethyl auristatin E which is connected to the antibody is then released where it can act as antimicrotubule agent disrupting the microtubule network leading to G2/M phase arrest
What are dendritic cell vaccines?
This is when professional antigen presenting cells are used to present tumour antigens
The APCs can be fed tumour lysates of apoptotic bodies, which has the advantage of not requiring the tumour specific antigens to be isolated first
How is the efficacy of anti-tumour vaccines improved?
There may use of a danger signal with adjuvants such as GM-CSF being coupled to the antigen
Other danger signals such as toxoid can enhance the humoral and cellular response against the tumour
What is cellular therapy?
This is when there are infusions of large numbers of lymphocytes
These have the disadvantage of the fact they neeed to be individualised for each patient and tumour are one off shot and the tumour may mutate
