4: Immunology of cancer Flashcards
(21 cards)
Role of immune the system: summarise evidence for the importance of tumour surveillance by the immune system, and explain how immune responses to tumours have some similarities with those to virus infected cells
Tumour antigens: explain the concept of tumour-associated antigens giving named examples, and explain how they differ from tumour-specific antigens
Immunotherapy: summarise approaches being used and developed for tumour immunotherapy, including antibody-based therapy, tumour vaccination and immune checkpoint blockade
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Evidence for importance of tumour surveillance by immune system?
Paraneoplastic Cerebellar Degeneration
Autoimmune disease where Immune response to breast tumour makes anti-CDR2 antibodies which goes to brain to affect neurons in cerebellum which have similar/same antigens as breast tumour cells
Destroys Purkinje cells
What does PCD teach us?
- Tumours can express antigens not expressed by normal tissue (i.e. breast tumours)
- Immune system can detect abnormally expressed antigens and attack the tumour
- In some cases this can result in auto-immune destruction of NORMAL tissues
Give circumstantial evidence for immune control of tumours
- Autopsies of accident victims showed microscopic colonies of cancer cells but no symptoms
- Patients ‘free of disease’ of melanoma, after many years used as donors for transplantation. Recipients developed tumours. Suggests donor had immunity but recipient did not
- Immunosuppression (e.g. in transplantation) increases risk of malignancy
- Men are twice as likely to die from cancer compared to women - possibly linked to fact that women usually have stronger immune responses
Describe the cancer-immunity cycle
- When tumour grows some cells die and release antigens
- These are carried by dendritic cells or other APCs via lymph to lymph node
- Antigens presented to re-circulating lymphocytes
- May activate adaptive immune response
- Activated T-cells go via blood to the tumour
- T-cells go into tumour (TIL tumour infiltrating lymphocytes)
- TILs recognise the tumour antigen (presented by MHC molecule)
- TILs kill tumour cells, releases more antigens for detection
What are the requirements for activation of adaptive anti-tumour immune response?
Local inflammation in tumour
Expression and recognition of tumour antigens
Problems with immune surveillance of cancer?
May take tumour a while to cause local inflammation
Difference in normal and tumour cell antigens may be subtle
How are immune responses to tumours similar to immune responses to virus infected cells
In cancer T cells see ‘inside’ the cells by recognising tumour-specific antigens which are made INSIDE the cell and presented on the outside by MHC molecules
Same as viruses.
Examples of tumour specific antigens?
EBV and HPV viruses often cause cancer - tumour cells present viral antigens
Mutated cellular proteins - commonly proteins involved in regulation of cell cycle
Causes and examples of viral cancer
OPPORTUNISTIC - usually due to immunosuppression
EBV positive lymphoma - post-transplant immunosuppression
Kaposi sarcoma - HIV
HPV positive genital tumours (cervical cancer) -immunocompetent patients
Proteins associated with cervical cancer?
E6/E7 oncoproteins of HPV
They are intracellular antigens but can be processed and presented by MHC molecules
Target genes for HPV vaccination?
L1 L2 (late genes)
These are surface proteins of the virus
Incorporated into Virus-like particles
What are tumour-associated antigens
Different to tumour SPECIFIC antigens
TAAs are NORMAL SELF proteins which are aberrantly expressed
Since they are normal self, tolerance may need to be overcome to achieve immune response
Examples of TAAs
Cancer-testes (developmental) antigens
Found in male germ cells and placenta
e.g. MAGE family: melanoma associated antigens
Normally NOT expressed on adult tissue cells
HER2 - some breast cancers
Mucin-1 - overexpressed in many cancers
Carcinoembryonic Antigen (CEA) - normally only expressed in fetus/embryo
PROSTATE:
Prostate-specfic antigen (PSA)
Prostate-specific membrane antigen (PSMA)
Prostatic acid phosphatase (PAP)
Example of differentiation auto-antigens?
Many people have poor self-tolerance to TYROSINASE enzyme (melanin production, overexpressed in melanomas)
i.e. T-cells specific for tyrosinase are poorly deleted in the thymus
Immunotherapy against melanoma in mice causes skin de-pigmentation, because there would be an auto-immune response against tyrosinase
Problems with targeting TAAs for immunotherapy?
- Can generate auto-immune responses against NORMAL tissues
2. Tumour-induced tolerance to auto-antigens
Explain monoclonal antibody based therapy
- Naked (antibody on its own) e.g. Herceptin = anti-HER2
- Conjugated with radioactive particles or cytotoxic drug that does the damage instead of immune system
- Bi-specfic antibodies - genetically engineered to be able to bind to 2 different antigens
Explain cancer vaccination
PROVENGE for advanced prostate cancer (only approved cancer vaccine)
Patient’s WBC treated with fusion protein
Stimulates DC maturation and enhances PAP-specific T cell responses
Personalised tumour vaccine
Use RNA sequencing + WES (whole exome sequencing) on tumour cell
Use WES + HLA typing on patient’s normal cell
Identify mutations found in cancer cells
Predict peptides that bind to patient’s HLA molecules
Vaccinate against those specific antigens
Explain Immune checkpoint blockade
CTLA-4: Expressed on activated regulatory T-cells
PD-1: Expressed on activated T-cells (may be upregulated in tumours)
Anti-CTLA4/PD-1 antibodies seek to reduce/remove negative regulatory signals to indirectly enhance positive immune response
Explain Adoptive transfer of cells (ACT)
Take WBCs from patient with tumour
Expand Tumour infiltrating lymphocyte population in vitro
Re-infuse into patient
Example of genetic engineering in ACT?
Chimaeric Antigen receptors
Can be added to T-cells
Specific to tumour antigens
