Avoiding immune destruction Flashcards
what mouse model was evidence that tumours can be repressed by the immune system?
tumour transplantation models.
immunity was only seen in prophylactic immunization and not therapeutic
once a mouse had been implanted with the tumour, immunization with irradiated cancer cells did nothing to stop tumour growth
what does this mouse model support the existence of?
tumour associated antigens
immunosurveillance theory where carcinomas are constantly eradicated from the immune system
TF: macrophages are only anti tumour
false can be either depending on signals
how can macrophages be anti-tumour?
present the antigen to the T helper cell and trigger tumour cell killing by antibodies
which 2 signals can activate macrophages in a anti tumour way?
bacteria lipopolysaccharide
interferon gamma
what can trigger macrophages in a pro tumour way?
hypoxia and other physiological signals released by tumours.
macrophage subtype M__ promotes immune attack on tumours and the subtype M__ promotes tumour progression
M1
M2
what initiates the process of phagocytosis and destruction of infected cells by the immune system?
coating of mammalian cells by antibody molecules due to the cell presenting target antigens
what do natural killer cells do once the mammalian cell is covered by antibodies. what does this activate?
natural killer cells uses its Fc cell surface receptor to bind to the constant regions of the antibody molecules
this activates the NK cell which then destroys the target cell by releasing cytotoxic granules
what is antibody dependent cell mediated cytotoxicity
the way NK cells kill cells using cytotoxic granules, Due to antibodies being present on the surface of cells presenting antigens
which cells tend to notably present antigens?
dendritic cells
where do langerhans reside?
in the skin
what do langerhans do?
take up antigens by phagocytosis and takes them to the lymph nodes
here they mature to dendritic cells and present the antigen to T cells triggering an immune response against this antigen.
dendritic cells activate which cells?
Th and Tc
what happens when a dendritic cell finds a T helper cell which recognises the antigens it (the dendrite) is presenting
the T helper cell becomes activated which leaves to find B-cells also displaying this surface antigen
once the T helper cell finds a B cell presenting the antigen which the dentrite has presented to the T cell, what happens?
the B cell proliferates and differentiates into plasma cells which release antibody molecules
what is the interaction between dendritic cells and cytotoxic T cell precursors called? what effect does this have on the cytotoxic T cell precursors?
cross presentation
helps the precursors mature into active cytotoxic T cells
what do cytotoxic granules from Tc contain?
perforin and granzyme B
5 Mechanisms by which tumours escape immune recognition?
- low immunogenicity
- tumour treated as self antigen
- antigenic modulation
- tumour induced immune suppression
- tumour induced privileged site
explain how low immunogenicity can help the tumour
low expression of adhesion molecules or MHC’s so appear normal to the immune system
explain how the tumour is treated as a self antigen to evade immune response
APCs present the tumour antigens in the absence of co-stimulatory signals- this makes the T cells tolerative of them so they dont attack
explain how antigenic modulation helps a tumour evade the immune response
tumour initially express antigens which the immune system response to but can lose them by: ‘antibody induced internalisation’ or ‘antigenic variation’
2 ways tumours can lose their antigens to evade the immune system?
antibody induced internalisation
antigenic variation
what products can tumour cells make to suppress the immune system?
TGF-b
explain a tumour induced privileged site to avoid immune destruction
factors produced by tumour cells to create a physical barrier to the immune system
examples of factors produced by tumour cells to create a physical barrier to the immune system? what does this prevent?
collagen
lymphocyte access
Tregs cells are _____ in number in tumour tissues than in normal
higher
why are Tregs at higher number in tumour cells?
probably because the regulatory T cells are activated by a large number of self antigens which tumour cells secrete
how are T regulatory cells attracted to a tumour? what do tumour cells produce to attract?
tumour cells produce CCL 22 chemokine which bind to their receptor on T regs and attracts them to the tumour
what effect does tumour growth factor beta released by tumour cells have on Tregs
critical for the expression of transcription factors which regulate Tregs cell differentiation
once Tregs are recruited to the tumour what do they inhibit? EFFECT?
CD4 Thelper cells
CD8 cytotoxic T cells
CRIPPLE HOST ADAPTIVE RESPONSE TO TUMOUR
so T-regs in the tumour ME is _____ for the tumour
GOOD stops immune response by inhibiting Tcells
how do dendrites work?
bind antigens from viruses or bacteria and present them to T cells for the initial immune response
how can we target dendrites in therapy?
scientists fuse a cytokine to a tumour antigen, hope this will send a strong antigenic signal
then they grow the patient dendritic cells in an incubator and allow them to take up the fused cytokine tumour antigens
then revive these dendrites to the patient to let them present the antigen to the immune system and make the T cells mount an attack on the cancer cells
2 things that can be introduced to redirect T cells to have tumour specificity
- transgenic T cell receptors
2. chimeric antigen receptor proteins
what are chimeric antigen receptor proteins?
fusion proteins composed of an extracellular portion derived from an antibody
an intracellular signalling molecules derived from T cell signalling proteins
what can we target for a PROPHYLACTIC vaccine against human papilloma viruses?
capsid proteins L1 and L2 which interact with the surface molecules of epithelial cells to gain entry to the cells
As this is present during the initial infection they’re ideal targets prophylactically
what to target for a therapeutic vaccine against HPV
the E6 and E7 oncoprotein are expressed during viral infection
they are the primary targets in HPV vaccines.
what do the E6 and E7 oncoproteins do in a HPV infection
produced during the infection
bind the p53 and the retinoblastoma TSGs
Gemtuzumab mechanism of action?
anti CD-33 antibody
coupled with a toxin to treat AML
Toxin gets internalised and damages DNA
immunotherapy advantages?
- purity of the antigenic preparation hence sensitive and effective
- defined antigens that are simple to isolate from each patient
- minimal possibility for auto immune reactions
immunotherapy disadvantages?
- can only be used in a small number of cancers
- unclear which antigens are the best choice to mount an effective anti-tumour response in vivo
- patient specific antigens aren’t shared between patients even with the same cancer type
- need alot of tumour tissue to purify the antigen
