Tumour immunology and immunotherapy of cancer Flashcards
What is the relationship between immune response against tumour-expressed antigens and autoimmunity?
The immune system can, in principle, detect antigens on cancer cells, and as a result, launch an attack against the tumour. In some cases, the antigen may be expressed normally in other areas of the body. In these examples, an immune response against the tumour will also produce an immune response against the normal somatic tissues that contain the same antigen = autoimmune disease.
What circumstantial evidence is there that the body has immune control of tumours? (x4)
AUTOPSIES of accident victims have shown that many adults have microscopic colonies of cancer cells, with no symptoms of disease. Could immune control be the reason for this? Patients treated for melanoma, after many years apparently free of disease, have been used as donors of organs for transplantation. Transplant recipients have developed tumours. This could indicate that the donor had developed ‘immunity’ to the melanoma, but the transplant recipients had no such ‘immunity’. When we immunosuppress patients e.g. immunity, there is an increased risk of malignancy, indicating that the immune system plays at least some role in malignancy suppression. Men have twice as great chance of dying from malignant cancer as do women (women typically mount stronger immune responses).
What is the concept that malignant cells are controlled by the immune system called?
Immunosurveillance.
What is immunotherapy in the context of cancer treatment?
Immunotherapy tries to enhance immune responses to cancer.
REVISION: What are the key characteristics of T and B cells?
- T CELLS have an alpha-beta TCR and are MHC restricted. They can be split into Class I or Class II. (MHC molecules display cell contents for cell surveillance.)
- B CELLS produce antibodies and are capable of binding to a vast range of molecules.
What is the stepwise process of cancer development and induction of an immune response?
- Initiation of cancer results from multiple sporadic events over time (e.g. spontaneous DNA errors, chemical mutagens). These lead to genetic mutations which accumulate and affect the cell cycle. The result = tumour growth. 2. Once tumours reach a certain size, inflammatory mediators will be generated. 3. This inflammation recruits cells of the innate immune system (dendritic, macrophages, natural killer cells) – cells which can present the antigens derived from the tumours and activate immune responses (antigen presenting cells, particularly dendritic cells!). 4. An immune response is activated a delivered by the cancer-immunity cycle.
What is the cancer-immunity cycle?
- Some tumour cells will die, releasing antigens. 2. APCs – particularly dendritic cells, capture these antigens and present them –> cancer antigen presentation. 3. These cancer-antigen presenting cells migrate to draining lymph nodes and present cancer antigens to recirculating T cells. T cells may become activated as a result of this. 4. T cells traffic back into the blood to the site of the tumour. 5. Activated T cells infiltrate into tumours through the endothelial cell layer of blood vessel walls – they are called tumour-infiltrating lymphocytes (TILs). 6. T cells recognise the cancer cells. 7. Killing of cancer cells (more tumour cells die and release more antigens – hence, the cycle continues).
What are the requirements for activation of an adaptive anti-tumour immune response? (x2)
• You must have LOCAL INFLAMMATION in the tumour i.e. you can’t just have the antigen; you must have a secondary ‘danger’ signal too. This requires cancer to have developed by quite some bit. • You must have expression and recognition of tumour antigens that are different from normal self – otherwise, how does the immune system differentiate between cancer and self?
What are the problems with immunosurveillance of cancers? (x3)
• It takes the tumour a while to cause local inflammation (and therefore stimulate an adaptive immune response). Once an immune response has been triggered, cancer has already developed by quite a bit. • Antigenic differences between normal and tumour cells can be very subtle. Remember, cancer cells are variants of the original cell (from an accumulation of mutations) – so antigens can differ sometimes by only a small number of point mutations. Immune system needs to detect that! • An immune response to cancer imposes a strong IMMUNE SELECTION PRESSURE. Any tumour cell that develops that can evade the immune response (e.g. loses its ability to express MHC molecules, so no longer taken up by APCs and dendritic cells) will be able to ‘survive and reproduce’, and the whole cancer may evade the immune system as a result.
What is the concept of immunotherapy in cancers in relation to the problems with immunosurveillance?
Cancer Immunotherapy is…: If requirements for ‘spontaneous’ activation of the adaptive anti-tumour response are not met, can we ‘teach’ the adaptive immune system to selectively detect and destroy tumour cells?
How do mutations in cancer cells present to the immune system? Comparison to infections?
Mutations in cancer cells results in mutations in the proteins that are subsequently translated. MHC displays these INTRACELLULAR proteins on the cell surface = cancer cell ANTIGEN. These allow T-cells to ‘examine’ the contents of cancer cells and recognise tumour-specific antigens. MHC displays contents of cell for immune surveillance by T-cells in the same way for INFECTIONS too.
Similarities and differences between immune responses against tumours and infections?
Immune responses against tumours have some similarities with those against virus infected cells, in terms of mechanisms. However, tumours are much less inflammatory than infections, and therefore it is harder to generate lymphocyte responses against tumours than infections
What are tumour-specific antigens? Examples? (x2)
• When the contents of the cell presented on MHCs are specific to the tumour, and different from the contents of normal cells, they are called TUMOUR-SPECIFIC ANTIGENS. • For example, VIRUS PROTEINS and MUTATED CELLULAR PROTEINS: • VIRUS PROTEINS: there are some viruses associated with cancerous tumours, and these tumours therefore produce viral proteins e.g. Epstein Barr Virus (EBV) and Human Papillomavirus (HPV). These are not found in healthy cells, so T cells recognise those and target them. • MUTATED CELLULAR PROTEINS: DNA mutations in cancers produce mutated proteins. Where these proteins are sufficiently distinct from those that are normally produced by cells, they can be detected by the immune system. These mutated cellular proteins may also arise from chromosomal translocations, producing completely new cellular proteins e.g. Bcr-Abl.
Two types of cancer of viral origin? Examples. (x2 and x3)
• OPPORTUNISTIC malignancies in immunosuppressed individuals e.g. EBV-positive lymphoma in post-transplant immunosuppression, and HHV8-postitive Kaposi sarcoma in HIV. • Viruses causing malignancies in IMMUNOCOMPETENT individuals e.g. HTLV1-associated leukaemia/lymphoma, HepB virus- and HepC virus-associated hepatocellular carcinoma, and Human papilloma virus-positive genital tumours.
What is the mechanism of HPV in Cervical Cancers? Treatment?
• High-risk HPV types can cause cancer in immunocompetent individuals. For example, HPV-16 is associated with cervical cancer. In these cases, the tumour cells express viral antigens – E6 and E7 oncoproteins – these internal proteins of HPV cause deregulation of the cell cycle and aberrant cell growth = cervical cancer. • These viral proteins are presented on MHC complexes on the cell surface. HPV VACCINE: Target antigens are incorporated into the HPV vaccine to mimic these viral proteins in the MHC complex, triggering a primary immune response. HPV vaccines are given prophylactically and have been successful and preventing cervical cancer from HPV.
What are the two uses of the HPV vaccine?
• PROPHYLACTICALLY. • THERAPEUTICALLY: in most who are not vaccinated, the immune system usually produces a strong enough response against the infection to prevent the development of cervical cancer. However, in less than 1% of unvaccinated individuals, HPV-16 infections still cause cancer where patients do not produce a strong enough immune response. In these patients, vaccines can still be used therapeutically to stimulate the immune response.
What are tumour-associated antigens (TAA)?
Are NORMAL CELLULAR PROTEINS, which are aberrantly expressed (i.e. in the wrong place, wrong time or wrong amount). Because they are normal self-proteins, for an immune response to occur, tolerance may need to be overcome (tolerance denotes deleting or at least regulating lymphocytes that are self-reacting – we want this to be overcome and we want an immune response against these cells!).
Examples of tumour-associated antigens? (x6)
• CANCER TESTES ANTIGENS: ectopically-expressed auto-antigens – silent in normal adult tissues except male germ cells. They have been described melanoma, liver and lung cancers. • MAGE PROTEIN FAMILY: ectopically-expressed auto-antigens – melanoma-associated antigens identified in melanoma and also expressed in other tumours. • HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR (HER2): overexpressed in some breast tumours. • MUCIN (MUC-1): membrane-associated glycoprotein, overexpressed in many cancers. • CARBINOEMBRYONIC ANTIGEN (CEA): normally only expressed in foetus, but overexpressed in a wide range of carcinomas. • Prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), prostatic acid phosphatase (PAP).
How is central tolerance produced? Subsequent aim in cancer treatment?
• T-lymphocytes mature mostly in the thymus. Here, there is negative and positive selection of T-lymphocytes. • Negative selections to remove autoreactive T cells, and positive selection occurs to keep self-MHC-restricted, self-tolerant T cells. • However, this process is not perfect, and we end up with some T cells with the potential of recognising self-proteins – though, in most cases, they do not become activated and do not cause problems. • In cancer treatment for TUMOUR-ASSOCIATED ANTIGENS, we aim to the activate these T-cells that have evaded negative selection in the thymus - IMMUNOTHERAPY.
What are the problems with targeting of tumour-associated auto-antigens for T-cell mediated immunotherapy of cancer? (x3)
• [Mentioned at the start.] We risk triggering an auto-immune response against normal tissues. In other words, when we activate T-cells against tumour associated antigens, we risk triggering autoimmunity against healthy tissues that also express the same antigen e.g. this is seen in local autoimmune depigmentation in melanoma patients. • There are no auto-reactive T cells that have evaded negative selection in the thymus, that can target the tumour-associated antigen in the first place. • Tumour-induced tolerance: tumours release factors which downregulate the immune response. This therefore reduces the chances of success of an immune response being triggered against tumour-associated antigens.
What APPROACHES are there being developed for tumour immunotherapy? (x5)
• Antibody-based therapy. • Therapeutic vaccination. • Immune checkpoint blockade. • Adoptive transfer of immune cells. • Combinations of all the therapies listed above.
How do antibody-based therapies work? (x3) Examples? (x1, x2 and x1)
• These therapies use MONOCLONAL ANTIBODIES. Monoclonal means single-specificity. There are three methods: • NAKED: antibody alone e.g. Herceptin uses antibody-HER2 on breast cancer cells. • CONJUGATED: monoclonal antibody is conjugated with RADIOACTIVE PARTICLE (deliver radiation to tumour) e.g. anti-CD20 conjugated with yttrium-90, or conjugated with a DRUG (deliver drug to tumour) e.g. Kadcyla uses anti-HER2 conjugated with a cytotoxic drug. • BI-SPECIFIC ANTIBODIES: genetically engineered to combine 2 specificities into one antibody e.g. anti-CD3 and anti-CD19 = Blinatumomab – used for B cell tumours.
How do therapeutic cancer vaccinations work? Example?
• Patient’s own white cells are treated with fusion proteins to simulate dendritic cell maturation and enhance T cell responses to attack the cancer. • e.g. Provenge is used for advanced prostatic cancer. White blood cells are treated with fusion protein consisting of two parts – prostatic acid phosphatase (PAP) and the cytokine GM-CSF. The activated product is returned to the blood.
How do personalised tumour-specific cancer vaccines work?
• Whole exome is sequenced and used to identify mutations in the tumour cell. • Computer programmes are used to predict the peptides that bind to the HLA molecules, and neoantigens are subsequently produced. • A personalised therapeutic vaccine is therefore produced, tailored to the specific mutations of the patient’s cancer, to increase the immune response.
