L17 - Tumour Immunology Flashcards
What has been proved about the immunogenicity of tumours?
Tumours themselves shown to be immunogenic as well as able to induce immune memory
What is cancer immunosurveillance?
The concept that the immune system can recognise precursors of cancer and, in most cases, destroy these precursors before they become clinically apparent
What is cancer immunoediting?
- The concept that the immune system edits the immunogenicity of tumours by a process of natural selection that may eventually result in the formation of a tumour. It consists of the 3 Es:
1 - Elimination - immune-mediated destruction of most cancer cells
2 - Equilibrium - a dynamic equilibrium between the immune system and any tumour cell that has survived the elimination phase. The immune response is enough to contain, but not eliminate, these cells
3 - Escape - the tumour cell variants selected in equilibrium now grow out in an immunologically intact environment
What signals are required for a T cell to become activated?
1 - A first signal is recognised through the T cell receptor in the form of a protein presented on MHC on an antigen-presenting cell
2 - T cells must also receive costimulation from CD80 & CD86, which bind to T cell CD28
Describe the process of generating an immune response to a tumour.
1 - Tissue damage at the site of a tumour results in tumour antigen release
2 - A dendritic cell presents this tumour antigen
3 - The dendritic cell travels to a lymph node and presents the antigen to many T cells
4 - The T cells whose T cell receptors recognise the tumour antigen on the dendritic cell undergo clonal expansion
5 - The selected T cells leave the node and enter the circulation to travel to the site of the tumour, where they elicit an immune response
List 5 mechanisms that explain why tumours originating in the body are not protected by tolerance to self antigens.
1 - Some proteins might become mutated during the formation of the cancer, such that they are no longer recognised as self antigens
2 - Some normal self antigens might be overexpressed, resulting in an immune response to those antigens
3 - Lineage-specific antigens might be inappropriately expressed in the tumour. Although these are self, an immune response is generated at the expense of damage to that lineage
4 - Abnormal post-translational modification of self proteins in the tumour
5 - The tumour carries a viral protein
How can an immune response destroy a tumour without targeting the tumour cells directly?
By targeting the tumour stroma, e.g. by identifying endothelial markers
What are the characteristics of a good target antigen for tumour immunotherapy?
1 - The antigen is tumour-specific (reduces toxicity of the immune response)
2 - The antigen is shared amongst other tumour types (the treatment is widely applicable)
3 - The antigen is critical for tumour growth / survival (to ensure there is a lack of antigen-loss tumour cell variants)
4 - There is a lack of immunological tolerance to the tumour tissue (to ensure that there maximally high avidity T cells are produced)
List 3 good examples of tumour antigens that are highly tumour-specific.
1 - Mutated self-proteins
2 - Viral antigens
3 - Cancer-testis antigens
List 2 good examples of tumour antigens that are commonly shared amongst other tumour types.
1 - Mutated self or vital proteins involved in oncogenesis
2 - Lineage-specific antigens (for multiple tumours within this lineage)
List 2 good examples of antigens that are critical for tumour growth / survival.
1 - Mutated self or vital proteins involved in oncogenesis
2 - Overexpressed self proteins
List 2 good examples of tumour antigens to which an individual will have a lack of immunological tolerance.
1 - Mutated self-proteins
2 - Viral proteins
By which mechanisms might tumours escape an immune response?
- Loss of MHC-I expression on tumour will prevent recognition by CD8+ T cells
- Reduced expression of proteins such as TAP1, LMP2, LMP7 & tapasin prevents processing & presentation of tumour antigen
- Loss of costimulatory molecules prevents T cell activation
- Loss of adhesion molecules such as ICAM1 prevents T cell binding well to target cell
- Loss of target antigen
- Inhibiting T cell infiltration
- Immunosuppression at tumour site
How can tumours inhibit T cell infiltration?
- Endothelin B receptor expression on tumour endothelium reduces T cell adhesion to vascular endothelium via prevention of ICAM modulation
- Nitrosylation of chemokines can keep T cells from entering tumour core
List 2 methods of inducing non-specific T cell stimulation as a therapy for cancer.
- Immunostimulatory cytokines can promote T cell growth
- Blockage of immunologic checkpoints can be used to increase T cell activation
