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Summary Chapter 12 +13
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This is a summary of chapter 12 + 13. With all of my summaries for this course I passed it with an 8!
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Chapter 12 Tumor immunology and immunotherapy + Chapter 13Inflammation
Before 2011: there is seen that the activation of the immune system by the bacteria
might led to anti-tumor immune response so would provide protection against tumors.
But the results in the clinic where disappointed
In 2011: this changed when Yervoy (checkpoint inhibitor) (ipilumumab) hit the
market. It showed that immunotherapy has some benefits.
The hallmark of tumor for avoiding immune destruction (cancer cells escape the
immune response and keep on growing) is added to the circle
Ipilumumab is an antibody directed against the immune checkpoint CTLA-4 on T-
cells. This lead to effective immune response against cancer and thus survival
Few year later: this is followed by Keytruda (pembrolizumab)
Pembrolizumab is an antibody directed against the immune checkpoint PD1 on T-
cells. This is an even more effective immune
response.
Mellman cancer immunity cycle
Antigen release from dying tumor cells because of
necrosis → antigens are taken up by the dendritic
cells (professional antigen presenting cell (APC))
and the dendritic cells are active → dendritic cells
migrate to the lymph node → T cells become
active, once T cell is active it kill cells.
Checkpoint is on the surface of activated T-cells
that can recognize antigen presenting cell
(APC)/tumor through interaction with MHCI
through T-cell receptor (TCR) → T cells migrate
via the bloodstream to the tumor → T cells interact with tumor cells
and kill them
In normal: there are no antibodies which can take way the breaks
(checkpoint). Once a T-cell is activated it kill cells through the
checkpoint this stops at a moment.
In cancer: antibodies (ipi and pembro) take away the breaks
(checkpoints) Thereby making sure that there is an effective T-cell
response and that these T-cells stay activated and proliferate so
they can actually fight against the cancer
Cancer/tumor antigens
3 characteristics:
1. Tumor specificity; only expressed in tumor NOT in normal
cells
2. No central tolerance; T-cells must have high affinity for them
3. High prevalence in multiple patients: so you can design
immunotherapy with is applicable for many patients
, 2 types:
1. Tumor-associated antigens
a. Overexpressed antigens(e.g.
EGFR/Her-2/neu); are
expressed in normal cells but
overexpressed in cancer →
variable tumor specificity / high
central tolerance / high
prevalence in multiple patients
b. Cancer testis antigens (e.g. NY-ESO1, MAGE-A3)); are expressed in
sperm cells and developing embryos but not in normal adult tissues.
They are re-expressed in cancer cells due to demethylation → good
tumor specificity / low central tolerance / high prevalence in multiple
patients
2. Tumor-specific antigens
a. Oncoviral antigens → ideal tumor specificity / no central tolerance / high
prevalence in multiple patients
b. Shared neoantigens (e.g. Ras); neoantigens (new antigens that derive
from mutations on the DNA) that are not specific for each patient →
ideal tumor specificity / no central tolerance / high prevalence in
multiple patients
c. Private neoantigens (e.g Ras); neoantigens (new antigens that derive
from mutations on the DNA) that are specific for each patients → ideal
tumor specificity / no central tolerance / low prevalence in multiple
patients
Tumor types that response best to immunotherapy:
- Are tumor that induce mutations on the DNA.
Neoantigens are antigens that derive from mutations
on the DNA → melanoma/ lung cancer
- Are tumor that are heavily infiltrated by T-cells
o Hot tumor: melanoma → there are T-cells
o Cold tumor (T-cell excluded tumor): pancreas → there are no T-cells
How does it all start?
Immature dendritic cell; found throughout the body. Have receptors that recognize
danger– IL-10, VEGF, IL-6, Prostaglandins (PGE), M-CSF and IDO)
Steps that lead to activation of dendritic cells:
- Toll-like receptors (TLR) bind to specific subunits of bacteria/viruses
Ligand for TLR can be found on the surface other in endosomes this is
dependent on the type of TLR ligands that they recognized.
TLR4: recognizes LPS expressed by bacteria → MyD88 gets
phosphorylated→ lead to intracellular pathway activation → lead to
transcription program which lead antiviral immune response, T cell stimulation
and inflammation
TLR3: recognizes viral dsRNA → MyD88 gets phosphorylated → lead to
intracellular pathway activation → lead to transcription program which lead
antiviral immune response, T cell stimulation and inflammation
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