lecture 8 - Immunotherapy Flashcards
What principles are immunosurveillance built on?
Self-tolerance - B and T cells against self-antigens are discarded prior to maturation to avoid autoimmunity
Immunity against foreign (non-self) antigens to generate an immune response
However, in cancer we need self-immunity
How do tumour neo-antigens arise?
Cancer cell mutations can lead to abnormal proteins that can be broken up into peptides
These peptides can be perceived as non-self and generate an immune response if they are displayed on the surface of the cancer cell
Neo-antigens need to be presented by MHC on the cell surface
However, the immune system can paradoxically constrain and promote tumour development and progression
What are the three phases of cancer immunoediting?
Elimination, equilibrium and escape
Cancer immunoediting happens during cancer progression, but also in patients receiving anticancer immunotherapies
What is the elimination phase of cancer immunoediting?
Tumours are recognised and eliminated by the innate and adaptive immune response
Macrophages and NK cells can recognise and kill cancer cells
T cells and antibodies (B cells) recognise tumour-associated antigens - CD8 cytotoxic T cells
How do natural killer cells play a role in the elimination phase?
NK cells are part of the first line of defence against tumour cells and their activation depends on activating and inhibitory signals received from cell surface receptors
Normally, NK cell activation is inhibited by ligands expressed on healthy cells that bind to inhibitory receptors on NK cells
A reduction in the expression of these ligands or an up regulation of stress-induced ligands that can occur in tumour cells leads to NK cell activation, and results in the production of IFN-gamma and direct cytotoxic activity against these cells
How do Th1, 2 and 17 cells play a role in the elimination phase?
Th1 cells are a subset of effector CD4 cells whose differentiation is activated by IL-12
They are mainly involved in macrophage activation, but can also suppress Th2 responses and promote cell mediated cellular cytotoxicity
Th2 - initiate B cells to produce antibodies and promote mast cell and eosinophil function, suppresses Th1 responses
Th17 - a subset of CD4 T cells which secretes IL-17, which in turn promotes recruitment of neutrophils
How do cytotoxic T cells play a role in the elimination phase?
CD8+ are a T cell type that can induce cell killing
they create holes into the membrane of the target cell, lysing the cells
What is the equilibrium phase of cancer immunoediting?
Rare tumour sub clones with further mutations survive elimination, and the tumour progresses into the equilibrium phase
this is where selection pressures instigate new tumour cell genetic variants
Net tumour growth is limited and can be stalled
What is the escape phase of cancer immunoediting?
Can select for tumour subclones with reduced immunogenicity that can evade immune recognition and destruction (e.g. decrease in IFNg secretion)
There is an up regulation of surface molecules
CD8+ T cells become exhausted or dysfunctional due to persistent antigen exposure and chronic T cell receptor signalling
Characteristics of exhausted T cells include up-regulated and sustained expression of multiple inhibitory immune checkpoint receptors, reduced proliferation and decreased production of effector cytokines
Which immune cells are tumour-promoting and which are tumour-suppressing?
Promoting - Treg cells, M2 macrophages, MDSC
Suppressing - NK cell, M1 macrophage, dendritic cell, B cell, TRM cell, CD4+ T cell and CD8+ T cell
What are the difference between M1 and M2 macrophages?
M1s are pro-inflammatory - they are present at the elimination phase and keep the tumour in check
M2s are resolving macrophages - they do not attack the cancer cells, but they support the environment that helps the tumour cell
What are the function of Tregs?
Subset of CD4+ T cells - they have immunosuppressive properties that are important for maintaining immune homeostasis and self-tolerance, limiting inflammation and preventing autoimmunity
They also inhibit multiple immune cell types including CD8+ and CD4+ effector T cells, NK cells and DCs
In cancer, Tregs inhibit the anti tumour immune response through inhibition of tumour-suppressing immune cells
What are the roles of myeloid-derived suppressor cells?
MDSCs are a population of immature myeloid cells with immunosuppressive properties
They produce high levels of IL-10, TGF-beta and other cytokines which inhibit NK cells, CD8+ and CD4+ cells, and promote expansion of regulatory T cells
What are hot and cold tumours?
Hot tumours have high levels of tumour-infiltrating lymphocytes
Cold tumours contain high levels of immunosuppressive cells
Hot tumours often have a high mutational load - this means they often have higher levels of neoantigens that can be recognised by the immune system
What is the aim of immunotherapy?
To get more immunosuppressive cells and less of the promoting ones
