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.
What is the tumour immunology cycle?
-Tumours are characterized by mutations that lead to neoantigens specific to the tumour. Some tumours (HPV positive tumours) express unique viral antigens that set the tumour apart from normal tissue
-Dendritic cells present tumour antigens to T cells, if all goes well, the T cell will be activated and return to the tumour to kill tumour cells based on recognition of tumour-specific neoantigens or viral antigens
-However, tumours are smart and have figured out ways to escape the immune system or turn off the immune response; the goal of immunotherapy is to block immune escape
What is immune surveillance?
Immune surveillance is the theory that the immune system patrols the body not only to recognize and destroy invading pathogens but also host cells that become cancerous. Perhaps potential cancer cells arise frequently throughout life, but the immune system usually destroys them as fast as they appear. There is some evidence for this attractive notion. There is also evidence that the immune system mounts an attack against established cancers although it often fails. Possibly cancer cells are destroyed by the immune system as quickly as they develop.
How does immune surveillance work?
For immune surveillance to work cancer cells must express antigens that are not found on normal cells. Otherwise the immune system would see them as self and be tolerant of them. Some examples of tumour antigens:
-Antigens expressed by cells infected with oncogenic viruses, such as HPV (cervical cancer)
-KSHV the virus that can cause Kaposi’s sarcoma
-Epstein-Barr virus (EBV) predisposes to Burkitt’s lymphoma
-Hepatitis B predisposes to liver cancer
-HER2 (Human Epidermal growth factor Receptor 2) a growth factor receptor found on some tumour cells (some breast cancers, lymphomas). HER2 is also known as ERBB2
Host gene products that are structurally altered by somatic mutation. A mutated version of the gene (IDH1) encoding the protein isocitrate dehydrogenase type 1 is frequently found in several types of cancer. In mice, a vaccine presenting a peptide including the mutant sequence elicits a Th1-cell response that slows tumour growth.
A mutated version of a protein that binds with ERBB2 expressed in a carcinoma is recognized by the patient’s tumour infiltrating lymphocytes (TILs), and these Th1 cells can destroy the tumour cells.
What happens in immunodeficient mice?
Immunodeficient Mice:
Mice with genes needed to make Th1 cells and/or cytotoxic T lymphocytes (CTLs) and/or NK cells knocked out. They have an increased incidence of spontaneous tumours are more susceptible to the induction of tumours by chemical carcinogens.
What is evidence of immune surveillance with mice?
Normal Mice:
-Mice with a normal immune system are given very low doses of a chemical carcinogen a few develop rapidly-growing tumors but many do not. However, it turns out that malignant cells are present in healthy animals as well but something is holding them in check. That appears to be the adaptive immune system because treating them with monoclonal antibodies targeting CD4+ T cells (Th1) and CD8+ T cells (CTL) or monoclonal antibodies against interferon-gamma (IFN-γ) or interleukin 12 (IL-12) causes fatal tumors to begin to grow in many of them.
Immunodeficient Humans:
Humans with depressed immune systems have an elevated incidence of cancers such as Kaposi’s sarcoma (AIDS) and B-cell lymphomas (in both AIDS patients and transplant recipients).
Immunocompetent Humans:
Cancer patients whose tumors contain large numbers of tumor-infiltrating lymphocytes (TILs), e.g., Th1 cells and/or cytotoxic T lymphocytes (CTLs) and/or NK cells cope with their disease better than patients with only small numbers of these cells.
Why does immune surveillance fail?
Perhaps most of the time it doesn’t. Perhaps visible cancers represent a rare failure of a system that has been eliminating transformed cells throughout life. But if that is true, what led to the rare failures? If a cell succeeds in starting down the path leading to uncontrolled mitosis, it may acquire somatic mutations that increasingly protect it from attack by the host’s immune system. For example:
-Reduced expression of tumour antigens
-Reduced expression of class II MHC molecules needed to display tumour antigens to CD4+ Th1 cells
-Class I MHC molecules needed to display tumour antigens to CD8+ cytotoxic T lymphocytes (CTLs)
-Reduced efficiency of loading antigenic peptides into MHC molecules
-Secretion of immunosuppressive cytokines (e.g., Transforming Growth Factor-beta — TGF-β)
-Recruitment of immunosuppressive Treg cells
Whatever the importance of the body’s innate response to cancer cells, there is no longer any question that the immune system can be manipulated to help against tumours.
What does interferon gamma do?
It is produced by antigen-activated TH1 cells. In addition to its antiviral effects, IFN gamma enhances MHC class 1 on many cells and increases MHC class II and B7 expression on B cells and macrophages, thereby enhancing antigen presentation.
What does IL-12 do?
It activates NK cells.
How can viral cancers avoid the immune system?
It’s possible that the tumors seen in immunosuppressed transplant recipients are of viral origin (Kaposi sarcoma associated with the human herpes virus, squamous cell carcinoma of skin associated with HPV or EBV). If so, the problem could be that the immune system cannot get rid of the virus, rather than not getting rid of the tumour. A revealing example: Both recipients of a cadaver kidney from a woman, who had been seemingly cured of her melanoma 16 years before, developed melanomas that were genetically the woman’s. The recipient’s failure to reject those cells was because of the immunosuppressive measures they were receiving so as not to reject her kidney. She must have harbored melanoma cells all those years with her immune system keeping them in check.
