Tumour Immunology 7/03/23 Flashcards
Why can the immune system not detect and destroy cancer cells?
-Cancer hasn’t got PAMPs (pathogen–associated molecular patterns) that allow the immune system to make the immune system aware of a problem (except in HPV and cervical cancer)
-Cancer is derived from normal cells (SELF), and our body is trained to be tolerant of normal cells (so don’t get autoimmune reactions occurring). However, in addition to this passive tolerance, cancers are smart, and they maintain a tolerogenic state by secreting a variety of factors to maintain this tolerance
How do cancer cells avoid the immune system?
-Cancer cells are self cells so the adaptive immune cells (T cells) do not usually enter tissues unless they have been recruited there by innate cells as a result of PAMP-initiated inflammatory response. As cancer cells lack PAMPs, the innate cells cannot bind them, and consequently cannot recruit the adaptive immune cells to the tissues. Therefore, even if a mutation has caused the expression of molecules that would not normally be expressed in the body, it won’t cause an adaptive immune response unless it is co-stimulated.
-Dendritic cells in the tissues are immature and do not migrate to lymph nodes to present antigen unless activated by a PAMP or another source of pattern recognition receptor stimulation such as DAMP (danger associated molecular pattern). Therefore a tumour neoantigen will be ignored by the immune system unless presented by a mature dendritic cell so tolerization to the tumour antigen will occur-this occurs passively.
-Tumours also deliberately induce tolerance by secreting factors such as IL-10 and VEGF to make nearby dendritic cells tolerant. Tumours also secrete other factors like TGF-beta to suppress T cell activation, proliferation and differentiation. This is known as active tolerization.
How does the immune system actually support cancer growth?
-Tumours often contain many tumour associated macrophages and neutrophils and the tumours have recruited them to help the tumour cells proliferate and progress.
Tumours secrete inflammatory cytokines and chemokines (such as IL-1, IL-6, IL-8) to drive tumour growth.
-These inflammatory mediators recruit neutrophils and macrophages which produce cytokines that promote proliferation of the tumour and angiogenesis. The tumour associated inflammatory cells, especially macrophages produce reactive oxygen and nitrogen species, resulting in DNA mutations that drive disease progression and metastasis.
What are tumour antigens?
Derived from normal proteins to which the immune system is not tolerant and becomes immunogenic when expressed by the tumour.
What immune responses occur to deal with cancer cells?
Immune responses to tumours do occur but they are modest. This is partly due to evasiveness of tumours as a result of their genomic instability, but also due to an acquired state of immune tolerance to the tumour. For the immune system to mount an effective anti-tumour response, the tumour must express molecules that are not normally found within the body or fail to express molecules that are normally present on healthy cells. MHC class 1 molecules are displayed on the surface of all nucleated cells, however, failure to express MHC molecules is one of the criteria natural killer cells use to select target cells for attack so NK cells may play an important role in immune surveillance.
The ideal tumour antigen would be expressed by cells of the tumour, but not by normal cells, however, this is not what is found. Generally tumour proteins represent nonmutated proteins or other molecules that are aberrantly expressed by the tumour. Also due to the genomic instability of the tumour, there is a lot of mutations that arose later in the tumour and will not be shared by individuals (this makes them less useful for therapeutic intervention).
How do viral antigens play a role in cancer?
Some tumours develop as a result of oncogenic viral infection. Epstein Barr Virus (EBV) in lymphomas, Human T cell leukaemia virus 1 (HTLV1) in leukaemia and human papilloma virus (HPV) in cervical cancers. After infection, the viruses express genes homologous to cellular oncogenes which encode factors affecting growth and cell division. Expression of these genes therefore leads to potentially malignant transformation. All tumours induced by a given virus should carry the same surface antigen.
How the the expression of normally silent genes help diagnose a cancer?
In cancer, sometimes genes which are normally switched off in a cell type are expressed. Sometimes these encode differentiation antigens that are normally associated with an earlier developmental stage. Oncofoetal antigens are antigens that are found on embryonic cells and on tumour cells, for example, carcinoembryonic antigen (CEA) in colon cancer. MAGE-1 is not expressed in normal tissues except for germline cells in testis so when this is expressed it indicates presence of a tumour. This can be used as a reliable tumour marker.
What role do mutant antigens play in cancer?
Mutated peptides have been identified in human tumours, for example, the gene encoding the cell cycle checkpoint protein p53 is a hotspot for mutations in numerous cancers. The mutant forms of p53 are inactivating or loss of function mutations, that fail to arrest division of cells that have suffered DNA damage, and which would normally cause cell cycle arrest or apoptosis of the cell. RAS mutations are normally point mutations usually causing single amino acid substitutions in codons 12,13 or 61. These mutations generate constitutively active forms of RAS that promote increased rates of cell division through the MAPK pathway. RAS mutations have been identified in 40% of human colorectal carcinomas and >90% of pancreatic carcinomas.
What changes occur in cancer cell surface carbohydrates?
Cancers often present abnormal carbohydrate structures on the cell surface. Sometimes they are missing, sometimes they are expressed (but absent on progenitor cells). Changes in surface carbohydrate can affect the metastatic potential of the tumour.
How are antigenic cancers seen by the immune system?
Tumours can be antigenic and there are several reasons for this:
-Mutation tumours have hundreds or thousands of mutations. If a mutation results in a novel peptide being generated the tumour may become immunogenic
-Some tumours re-express molecules that are normally found in the foetus (and adult testis). These are known as the oncofoetal antigens. Immunological tolerance requires a continuous supply of antigen being available to the immune system. New T cells are being formed continually and can only be tolerized if they see antigen
-Some tumours are induced by viruses. If the viral genome is incorporated into the host genome, viral proteins can be made. These are “foreign peptides”
-We are not tolerant to all cellular proteins. Some are present in too small an amount to induce tolerance. However, if expressed in large amounts by tumours they could then cause an immune response. Sometimes, less than 10 MHC class I molecules on a cell need to carry a particular peptide for it to be susceptible to CD8 T cell killing.
What is an example of a tumour specific antigen which contains tumour specific mutations?
In melanoma the tumour antigen is MART2 in the A1 HLA restriction.
What is an example of a tumour specific protein which contains tumour specific mutations?
In CML the tumour protein BCR-ABL1 fusion protein in the DR4, B8, and A2 HLA restriction.
What is the chimeric protein produced in melanoma?
AcloneofCD8TcellswasisolatedfromamelanomapatientandshowntorecognizeanonamerpeptidederivedfromamelanocyteglycoproteinandpresentedbyHLA-A*32:01.Thesequenceofthepeptidedoesnotcorrespondtoacontiguoussequenceinthemelanocyteglycoproteinbutisafusionofresidues40–42withresidues47–52.Thischimerawasgeneratedintheproteasomebypeptidesplicingduringtheproteolyticdegradationoftheglycoprotein.
Why do cancer causing viruses cause cancer in only some cases?
Only a minority of people infected with an oncogenic virus develop cancer-meaning the viruses must work together with something else to cause cancer. Some viruses may cause cancer directly. Kaposi’s sarcoma is restricted to people who are immunosuppressed due to infection with HIV. B lymphoma is caused by EBV infection or patients receiving immunosuppressive drugs following organ transplantation.
What are immune privileged sites?
Genes encoding cancer/testis antigens are concentrated on the X chromosome. Thirty-eight different types of cancer/testis (CT) antigen have been defined and numbered in a CT series analogous to the CD series of differentiation antigens. Genes encoding 17 of the 38 CT antigens are on the X chromosome and the others are distributed between 11 autosomes, none of which has genes for more than three CT antigens. Sites with immune privilege areanatomical regions that are naturally less subject to immune responses than most other areas of the body. Immune-privileged sites include the central nervous system and brain, the eyes, and the testes.
