Clinical Immunology Evelien Floor
HC5 Cancer
Tumor immune surveillance
Cells involved in tumor immune surveillance
The immune system plays an important role in tumor formation. One important hallmark of cancer is
therefore: avoiding immune destruction. Tumor immune surveillance is also called cancer immuno-
editing. Normal tissue is constantly under stress in our body due to for instance pathogens. Those cells
can transform to tumor cells who express tumor antigens. The immune system uses a lot of cells to
attack those tumor cells (macrophages, NK cells, CD4+ cells, CD8+ cells). All those cells surround the
tumor cells and eliminate them from our body. Hopefully, in the end there will be normal tissue again.
Sometimes this process fails because the tumor cells acquired some characteristics that made them
resistant for immune cells. Then, the tumor cells can grow out into tumors. The cells start to divide
and a heterogenous tumor is formed. These tumor cells express a lot of different factors: for instance
PD-L1 that inhibits T cell function. Under the microscope you can almost always see an immune cell
infiltrate. This immune infiltrate is trying to attack the tumor but this is not successful.
Different cytotoxic cells are involved in tumor immune surveillance:
• Innate immunity (phase 1)
o M1 macrophages/neutrophils
o Natural killer cells (NK cells)
o NK-T cells (CD3+)
o gd-T cells
• Adaptive immunity (phase 2)
o Cytotoxic T lymphocytes (CD8+ T cells)
o B cells
Red cells are all called cytotoxic lymphocytes.
1
, Clinical Immunology Evelien Floor
Cytotoxic T lymphocytes
Depletion of CTLs in mice results in spontaneous formation of
tumors. This indicates that those cells are important in tumor
immune surveillance. CTLs require activation commonly in the
lymph nodes. In the lymph nodes the tumor antigens are
presented on MHC-I molecules of APCs and CTLs will bind to this
tumor antigen and get activated. In the periphery the CTLs
recognize the exact same peptide on the tumor cells which
results in killing of the cells.
Natural killer cells
NK cells function in a different way, they are always present in
different tissue types for surveillance and detection of foreign
molecules. They need cytokines to increase their number. NK
cells predominantly recognize MHC-I molecules which are
present on all cells. In case MHC-I is present, this is a signal to
not kill this cell. Some tumor cells don’t express MHC-I because
of downregulation, so NK cells can recognize this. This way, the
tumor cells become a target for NK cells and will be killed.
Killing of tumor cells by cytotoxic lymphocytes
Three main killing mechanisms that cytotoxic lymphocytes use:
1. Death receptor pathway à TNF-receptor family:
o Fas – Fas-ligand
o TNFR1 – TNF
o TRAIL – TRAIL-R1/R2
2. Granule-exocytosis pathway à exocytosis of lytic granules
o Pore forming protein (perforin)
o Granule associated enzymes (granzymes)
3. (IFN-g pathway à very weak)
Death receptor pathway
The death receptor pathway can get activated via an extrinsic or intrinsic signal and takes 16-24 hours
to kill a cell. First there is recognition of a tumor cell MHC-I (CTL) or via NK cell receptors. This results
in the crosslinking of the death receptor with its ligand (extrinsic). Afterwards there will be recruitment
of procaspase-8 to the intracellular part of the receptor forming active caspase-8. Caspase-8 activates
caspase-3 which results in apoptosis.
An intrinsic signal is
mitochondrial stress induced
by activation of Bid which
causes permeabilization of
mitochondria. This results in
the efflux of cytochrome c into
the cytoplasm. Cytochrome c is
involved in the formation of the
apoptosome. The apoptosome
activate caspase-3 which
results in apoptosis.
2
HC5 Cancer
Tumor immune surveillance
Cells involved in tumor immune surveillance
The immune system plays an important role in tumor formation. One important hallmark of cancer is
therefore: avoiding immune destruction. Tumor immune surveillance is also called cancer immuno-
editing. Normal tissue is constantly under stress in our body due to for instance pathogens. Those cells
can transform to tumor cells who express tumor antigens. The immune system uses a lot of cells to
attack those tumor cells (macrophages, NK cells, CD4+ cells, CD8+ cells). All those cells surround the
tumor cells and eliminate them from our body. Hopefully, in the end there will be normal tissue again.
Sometimes this process fails because the tumor cells acquired some characteristics that made them
resistant for immune cells. Then, the tumor cells can grow out into tumors. The cells start to divide
and a heterogenous tumor is formed. These tumor cells express a lot of different factors: for instance
PD-L1 that inhibits T cell function. Under the microscope you can almost always see an immune cell
infiltrate. This immune infiltrate is trying to attack the tumor but this is not successful.
Different cytotoxic cells are involved in tumor immune surveillance:
• Innate immunity (phase 1)
o M1 macrophages/neutrophils
o Natural killer cells (NK cells)
o NK-T cells (CD3+)
o gd-T cells
• Adaptive immunity (phase 2)
o Cytotoxic T lymphocytes (CD8+ T cells)
o B cells
Red cells are all called cytotoxic lymphocytes.
1
, Clinical Immunology Evelien Floor
Cytotoxic T lymphocytes
Depletion of CTLs in mice results in spontaneous formation of
tumors. This indicates that those cells are important in tumor
immune surveillance. CTLs require activation commonly in the
lymph nodes. In the lymph nodes the tumor antigens are
presented on MHC-I molecules of APCs and CTLs will bind to this
tumor antigen and get activated. In the periphery the CTLs
recognize the exact same peptide on the tumor cells which
results in killing of the cells.
Natural killer cells
NK cells function in a different way, they are always present in
different tissue types for surveillance and detection of foreign
molecules. They need cytokines to increase their number. NK
cells predominantly recognize MHC-I molecules which are
present on all cells. In case MHC-I is present, this is a signal to
not kill this cell. Some tumor cells don’t express MHC-I because
of downregulation, so NK cells can recognize this. This way, the
tumor cells become a target for NK cells and will be killed.
Killing of tumor cells by cytotoxic lymphocytes
Three main killing mechanisms that cytotoxic lymphocytes use:
1. Death receptor pathway à TNF-receptor family:
o Fas – Fas-ligand
o TNFR1 – TNF
o TRAIL – TRAIL-R1/R2
2. Granule-exocytosis pathway à exocytosis of lytic granules
o Pore forming protein (perforin)
o Granule associated enzymes (granzymes)
3. (IFN-g pathway à very weak)
Death receptor pathway
The death receptor pathway can get activated via an extrinsic or intrinsic signal and takes 16-24 hours
to kill a cell. First there is recognition of a tumor cell MHC-I (CTL) or via NK cell receptors. This results
in the crosslinking of the death receptor with its ligand (extrinsic). Afterwards there will be recruitment
of procaspase-8 to the intracellular part of the receptor forming active caspase-8. Caspase-8 activates
caspase-3 which results in apoptosis.
An intrinsic signal is
mitochondrial stress induced
by activation of Bid which
causes permeabilization of
mitochondria. This results in
the efflux of cytochrome c into
the cytoplasm. Cytochrome c is
involved in the formation of the
apoptosome. The apoptosome
activate caspase-3 which
results in apoptosis.
2
