Immune system in tumor development, Destruction of cancer cells , -…
Immune system in tumor development
Main components of immune system:
CD4 T cell
T helper cells
CD8 T cell
T cytotoxic cells
Natural Killer cells
Release perforin which forms pore in the cell membrane of the tumor and granzymes which enters through the pore and destroy the tumor cell
Antigen presenting cell to T cells
Survey the environment to clear of any invading pathogen
How does the tumor cells get detected?
When the cells get mutated, the production of antigens may alter - increased/specific expression which gets recognised by immune cells and activate it
Tumor-specific antigens (TSA)
The antigens are
found in tumor cells but not healthy cells.
The DNA of the tumor cells have been altered, such that the amino acid sequence has changed which results in production of unique proteins. It will not be recognised as a self-antigen and the immune system that gets activated and recognise it as a tumour cell.
Tumor-associated antigens (TAA
) The antigens are found in
tumor & healthy cells but found more in tumor cells
Antigen-Presenting cells (APCs) : Dendritic cells, B cells, Macrophages
DC : The tumor cell will shed its surface antigen which gets recognised by dendritic cells and presented onto the MHC class II. The antigen on the MHC class II will be recognised by the T helper cells. The CD4 T helper cells gets activated & release IL2 cytokines.
How does cancer cells avoid the immune system?
Elimination: tumor cells are able to be destroyed by immune cells e.g NK cells
Equilibrium: Other remaining tumor cells undergo random mutation that does not express tumor antigen (HLA expression, stimulatory molecule)
Escape: The tumor cells that gain the most mutation are able to evade from the immune cells as they remain undetected
Repression of NKG2D Ligand
Expression of NK ligand by the tumour cells which will recognise the ligand and induce cell death.Through mutation, the cells will reduce expression of NKL to avoid getting detected by the NK cells
Repression of Antigen presenting
The MHC I will bind with the CD8 receptor which triggers the activation for cell death. The tumor cell
reduces expression of Class I, as it is crucial for CD8 T cell to recognise by MHC class I or the tumour antigen downregulate expression of tumour surface antigen
Inactivation of immune cells
T regulatory cells dampen the immune system by release immunosuppressive IL10 cytokines, to inhibit activation of naïve T cells. There will be no activation of Tc cells to kill the tumour cells. Treg express CTLA-4, a homolog of CD28, which downregulate B7 expression by APCs which decrease co-stimulatory signal that activates Tc cells. Thus, tumor cells will avoid getting destroyed.
Induce immunocyte apoptosis
Tumor cell express the FAS ligand which binds to Fas receptor on T cell and directly kill the T cells
Immune checkpoint inhibitor
Antibody blocks the PDL-1 or PD-1, which are co-inhibitory that prevents activation of Tc cells , and there will be no co-stimulatory inhibition and Tc cells will be able to kill the cancer.
Extracted dendritic cells are introduced to tumor antigens which are is introduced back into the patient. DC will present antigen to the T cells which induce immune response
Gene transfer into tumour cells to upregulate IL-2, IFNγ and B7. This will increase rate of destroying tumor cells by activating T cells.
Monoclonal antibodies are conjugated to toxin to the tumor cell and destroy it. It can also activate NK through the detection of antibodies attached to the tumor cell.
Adoptive T cell therapy involves isolation of tumor-specific cytotoxic T lymphocyte from the tumor. The T cells are modified in vitro and re-injected back into patients.
Destruction of cancer cells
B cell activation: With the T helper cells, the B cells get activated and will be able to differentiate into plasma cells which produces Antibodies. The antibodies will bind to the antigen surface of the tumor cells and the NK cell will recognise via the Fc receptor which will activate the ADCC pathway, opsonization where the macrophage consumes the tumor cells leading to cell death
CD8 T cell activation: CD4 helper T cells release cytokine IL2 which helps CD8 cytotoxic T cells proliferate. CD8 cytotoxic T cell will recognize the tumor as the tumor cells will have MHC class I, as it has a nucleus, where the Tc cells will recognize it and destroy the cell.
Kill through the engagement through the engagement of MHC class or FAS pathway – FAS/FASL , the cell that has the FAS ligand will be the one that kills the cell (the cytotoxic T cell will be the one that kills the tumor cells)