Immunology Flashcards
What role does the NK cell arm have in cancer immunosurveillance?
What are the 3 signals naive T cells need for activation?
What is the role of T cells in cancer immunity?
What are tumour associated vs specific antigens?
Tumour‐specific antigens arise from somatic mutations and are found only on cancer cells
What can tumour cells do if they are under selective pressure from the immune system?
What is the tumour micro environment?
The tumour microenvironment is an ‘ecosystem’ of tumour cells, immune cells, stromal cells and blood vessels. It is high in heterogeneity
Key immune cell populations are cytotoxic T cells, helper T cells, regulatory T cells, macrophages, myeloid derived suppressor cells (MDSC)
The cytokine milieu is also important
What are some m onoclonal antibodies to treat cancer?
Rituximab:
- Targets CD20
- Treatment for non-Hodgkin’s lymphoma
- Cytotoxic action – triggers antibody dependent cell mediated cytotoxicity by NK cells and macrophages; and classical complement pathway activation and formation of membrane attack complex
Trastuzumab (Herceptin):
- Targets HER2
- Treatment of HER2 -positive breast cancer
- Blocks dimerization and signalling (which induces cell proliferation) of receptor, inhibiting growth
What are some checkpoint inhibitor therapies?
CTLA-4:
- mediate its inhibitory effect during T cell activation by outcompeting CD28 for binding to B7 molecules on antigen-presenting cells, thus reducing co-stimulation
- Engagement drives immunoregulatory function of Treg and also deprives access of naïve T cells to co-stimulatory molecules
- CTLA-4 upregulated in naïve T cells after activation by the antigen presenting cell – prevents uncontrolled expansion of activated T cells and therefore excessive, damaging responses
- treatment most associated with colitis
PD-1:
- expressed by activated T cells
- Chronic exposure to antigen leads to high and sustained expression of PD-1 by T cells
- Signalling of PD-1 decreases T cell proliferation, cytokine secretion and cytotoxic activity. It can cause them to become anergic
What are the main HPV cancer causing types?
HPV 16 and 18 are the main cancer- causing HPV types
Viral protein E6 binds and promotes degradation of p53; E7 binds and inactivates Rb
Viral proteins therefore suppress apoptosis following DNA damage and facilitate progression through cell cycle
What are the approved CAR T cell therapies?
axicabtagene ciloleucel (Yescarta):
- For the treatment of adult patients with relapsed / refractory diffuse large B cell lymphoma
tisagenlecleucel (Kymriah):
- For the treatment of children and young adults with relapsed / refractory B cell acute lymphoblastic leukaemia
What are the mechanisms that CAR T cells kill via?
- Perforin & granzyme
- FasL (T cell) - Fas (target cell)
How are CAR T cells produced?
Genetic sequence encoding CAR ( recognition + signalling domains ) cloned and packaged into a lentiviral or retroviral vector
T cells activated and expanded by stimulating with anti-CD3 and anti-CD28 antibodies
Such viruses are good at transducing T cells (which can be a tricky cell type to transduce!)
End up with T cells that stably express the CAR
What are the side effects of CAR T cells?
CAR T cells produce lots of cytokines after recognition of tumour cells
IL-6, TNF-alpha, IFN-gamma
Quantitatively, main source of IL-6 is then cells of myeloid lineage – e.g., macrophages
IL-6 causes systemic inflammatory response. Can be treated with tocilizumab
