The Role of the Immune System in Cancer Flashcards
What is the normal immune surveillance in cancer?
- tumour cells initiate release of antigens
- = release of danger cytokines (INF-alpha and heat shock proteins)
- activation and maturation of dendritic cells to present tumour antigens to CD8 and CD4 cells
- subsequent T-cytotoxic destruction of the tumour
How do cancers evade the immune systems?
- tumour antigens immunogenic
- self antigens = potential tolerance
- evolved mechanisms which prevent immune rejection
What are the evolved mechanisms of cancer cells
- secrete inhibitory cytokines
- create unique microenvironment
- alter host immune system locally and systemically
- induce inhibitory T cell subsets
What is cancer immunoediting?
- functional cancer immunosurveillance processes and suppresses tumour growth
- dual role of immune system in interaction between host and tumour
What are the 3 characteristics of immunoediting?
- elimation of cancer cells by immune system
- equilibrium between cancer cells and immune system
- escape of cancer cells from immune system
How do tumours escape by natural selection?
- genomic instability of cells = natural selection of tumour variants = effective immunotherapy
What is the significance of increase T regulatory cells in cancer?
- suppressor T cells
- CD4+ T cells
- regulate immune response through antigen specific suppression of effector CD4+ and CD8+ T cells
- amount of T regs predict survival
- T cells in cancer exhausted due to chronic stimulation by cancer
- PD1 important marker increased on cell surface
What is cancer immunology?
- study of how cancer affects host immune system
What is passive cancer immunology?
administration of agent
- monoclonal antibodies
- transfer of effector cells
How are monoclonal antibodies produced?
- by single type of cell
- specific for an antigen
- inject human cancer cells into mice and mouse makes antibodies with are fused in lab = hybridoma
- hybridoma produces large quantities of antibodies
- mouse proteins chimeric or humanised
What are the different approaches of monoclonal antibody treatment?
- unconjugated (complement mediated lysis)
- coupled to toxins (immunotoxins)
- coupled to radioisoptopes (radioummunoconjugates)
How are monoclonal antibodies humanised?
- otherwise patients develop anti-mouse antibodies
- develop recombinant molecules which maintain antigen binding of murine MoABs coupled to human Ig backbone
What are the ideal targets for MoAb therapy?
- expressed on all tumour cells
- high copy number
- no mutations/variant antigens
- required for critical biologic function/cell survival
- not shed/secreted
- not modulated after antibody binding
How do MoAbs work?
- antibody dependent cell mediated cytotoxicity
- complement dependent cytotoxicity
- apoptosis
How does antibody-dependent cell mediated cytotoxicity work?
- Fc region on phagocytic cells (NK cells, macrophages, neutrophils)
- effector cells release mediators which damage and destroy malignant B cells
- malignant B cells phagocytosed
How does complement dependent cytotoxicity occur?
- membrane attack complex formed from activation of terminal portion of complement cascade
How does apoptosis occur?
Direct binding to a specific epitope directly affects tumour cells
How does rituximab work?
- chimeric
- targets protein called CD20 in normal and malignant B cells
- non-hodgkins lymphoma
How does trastuzumab work?
- humanised
- HER2+ positive patients
- dimerises HER2 receptors inducing apoptosis
What are bi-specific MoAbs?
bind to 2 different antigens
What are the methods of active cancer immunology?
- vaccination
- adjuvant treatments
What are the challenges of vaccination?
- choose right antigen
- choose right adjuvant
- generate right type of immune response
- elicit LT immune memory
- overcome immune defects in cancer bearing patients
What is active cancer immunology?
Induction of host immune response
What do prophylactic cancer vaccines do?
target cancer causing viruses
What are some current vaccine strategies?
- antigen/adjuvant vaccines
- whole cell tumor vaccines
- dendritic cell vaccines
- viral vectors and DNA vaccines
- idiotype vaccines
What is PD1?
Highly expressed in immune cells of cancer patients
- inhibitory receptors
What are immune checkpoint inhibitors?
- block immune checkpoints promoting endogenous antitumor activity
- e.g. block PD1 = restores T reg cell function
What is an example of immune checkpoint inhibition?
Chronic Lymphocytic Leukaemia
- CLL cell expresses PD-L1
- T cell contains PD-1 activated by PD-L1
- chronic activation = changes in surface molecules and effector function
What are some examples of approved PD-1 inhibitors?
- nivolumab
- pebrolizumab
