Immune system in cancer Flashcards
How does the body respond to the presence of tumour cells?
- tumour cells initiate the release of antigens (e.g. MAGE1 in melanomas)
- tumour cells and tumour antigens initiate the release of ‘danger’ cytokines (IFN-alpha and heat shock proteins)
- activation and maturation of dendritic cells to present tumour antigens to CD8+ and CD4+ cells
- leads to subsequent T cytotoxic destruction of the tumour
How can tumour cells evade the immune system?
- tumour antigens are weakly immunogenic
- there is a potential for tolerance of these antigens
prevent immune rejection by:
- secretion of inhibitory cytokines
- creation of unique microenvironment
- alteration of host immune system locally and systemically
- induction of inhibitory T cell subsets
What are the three Es of cancer immunoediting?
- Elimination: immune system eliminated cancer cells
- Equilibrium: cancer cells coexist with the immune system
- immune cells kill majority of cells, but some of the cells evolve to escape the immune system - Escape: cancer cells escape the immune system
What can determine length of patient survival, in terms of immune cells?
If the patient has few macrophages and many T-regulatory cells then they will survive longer
If the opposite is true then the patient will have a shorter survival time
Why can the level of T-regulatory cells determine length of patient survival?
- Treg cells are ‘suppressor t-cells”
- A subset of CD4+ T-cells involved in regulating the immune response through the antigen-specific suppression fo effector CD4+ and CD8+ T-cells
- Most Treg cells express CD4/CD25 and FOXP3
- Specific recruitment of regulatory T-cells in ovarian carcinoma and follicular lymphoma fosters immune privilege and predicts survival
What is an important marker for Cell exhaustion in cancer?
Increased PD1
What are the different forms fo cancer immunotherapy?
- Passive (adoptive)
- administration of agent - mAbs, transfer of effector cells
- -> T cells
- -> NK cells
- -> regulatory cells - Active
- induction of host immune response
- -> vaccination
- -> adjuvant treatment
What are the 3 different approaches to mAb treatment?
- Unconjugated - complement mediated lysis
- Coupled to toxins (immunotoxins)
- Coupled to radioisotopes (radioimmunoconjugates) - radiation therapy
Explain how mAbs work via antibody dependent cell mediated cytotoxicity.
- Antibodies bind to the tumour antigens
- effector cells such as neutrophils, natural killer cells and macrophages bind to the mAbs via their Fc receptors
- release cytotoxic agents that destroy the cell (triggered by crosslinking of receptors to mAbs)
- malignant cells are phagocytosed
Explain how mAbs work via complement dependent cytotoxicity.
- mAb binding to its specific target results int he recruitment of complement
- ultimately, this results in the generation of the membrane attack complex (MAC)
- MAC: punches holes in the B-cell plasma membrane causing lysis
Explain how mAbs work via apoptosis.
The binding of a mAb to its target cells results in the activation of specific intracellular signalling pathways that trigger apoptosis of the cell
may induce cell death by altering the physiological function of CD20 in B cells
What is a bi-specific mAb? Give an example.
mAb which is designed to bind to two different antigens
Examples:
- Blinatumomab = CD19/CD3 bispecific antibody –> binds to lymphoma cells and T cell to enhance cytotoxicity
What is PD1?
It is an inhibitory receptor on activated T-cells, B-cells, NK and myeloid cells
It inhibits t-cell activation when engaged by ligands (PDL1/2)
It is expressed on T-cells when exposed to tumours
Blocking PD1 may help prevent exhaustion of Cells
Give examples of types of cancer where PD1 is expressed/Tcells are exhausted?
Chronic lymphocytic leukaemia ]
NSCLC
Give examples of checkpoint inhibitors used in cancer.
Nivolumab
Pembrolizumab
