College aantekeningen
Lecture notes Tumor Immunology
- Instelling
- Vrije Universiteit Amsterdam (VU)
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Voorbeeld van de inhoud
Tumor immunologyPosted presentations are part of the exam
Synonymen > https://www.powerthesaurus.org/
re-writing > paraphraser
transalting > DeepL
HC 1 Basics of tumor immunology
Read chapter 15 of Weinberg prior for the lectures. Exam questions derive form the lectures and the
chapter.
- Lectures mostly cover the articles and their hot topics.
o Knowledge transfer and source for the exam.
- WG > research article
- Writing assignment > research article, writing an catchy abstract (sell the paper).
- Debating clubs (15% of the final grade)
o 3 minutes to state your statement
o Questions from team members and audience
o 1 minute to final statement
o Vote from the audience
- Journal clubs to discus and interpret the experiments and results > we have to tell the
teacher what is in the article + opinion.
o What did they do? Why did they do it? How did they do it? What did they find? What
did they conclude? Do you agree/disagree? Is anything missing?
Kahoot: Background knowledge of immunology
1. Not a secondary lymphoid organ > thymus.
2. Red pulp is not a structure of a lymph node.
3. Intra-cellular antigens are presented to CD8-positive T-cells.
4. Fc-dependent phagocytosis means that Fc-receptors are involved in uptake of antigen (or
pathogens).
5. Negative selection of thymocytes happen when T-cells recognise peptide and MHC with too
high affinity.
6. How far do human naïve T-cells in search of antigens collectively crawl in lymph nodes in one
day is >15000 km.
7. Take up antigens is not a characteristic of T-cells.
8. The recombinase enzymes RAG1 and 2 are expressed in immature B- and T-cells.
9. CD8 T-cell is not involved in MHC-II presentation.
10. CD4+ T-helper-1 cells function to activate macrophages to kill bacteria.
11. Loading of the peptides on MHC-II molecules happen when CLIP is released from MHC-II
molecule.
12. What is typical and unique for the adaptive immune system today? > the induction of
memory cells.
13. One type of MHC-molecule can bind different peptides that have the same anchor-sequence.
14. The effector function of antibodies is determined by the isotype of the antibody.
15. Cells that do not pass the positive selection in the thymus die from apoptosis.
16. B-cells can differentiate into plasma cells after activation by Th2 cells.
, 17. The first anti-PD1 mAb was made by organisation in NL. For what clinical indication was this
antibody initially developed? > rheumatoid arthritis.
18. High endothelial venules are important for migration of lymphocytes to the lymph nodes.
19. If an antibody were the size of a adult human, how big would the surface of a B-cell be? > a
small city.
20. Which is essential for antigen presentation in MHC-I? > peptide loading in the ER.
21. What do IgM and dimeric IgA have in common? > they are both multimeric antibodies
connected with a J-chain.
22. Antigen presenting cells express both MHC-I and -II.
23. Which of the following is the title of a published paper relating to the immunology of
pregnancy? > How to recognise a foreign submarine.
The difficulty with immunity and cancer is a double axis sword: it can kill tumor cells or help them to
grow. It is all about pushing the right buttons. Besides that, the microbiome also determines tumor
development.
Around 1890 it was found that a severe infection led to a shrinkage of tumors. So, the immune
system was activated by a bacterial infection. In the 70s and 80s lymphocytes were observed that
play a role in tumor response. The next big thing that was found around 2013 were the vaccine to
immune checkpoint inhibitor (PD-1 and CTL4 expression). Only the HPV vaccine is effective because it
is prophylactic (stop development before infection). However, most vaccines are therapeutic
meaning that it is given after the patient was diagnosed/sick.
- Vb: melanoma Yervoy and Keytruda increased a survival of 20% (anti-CTL4). Later
pembrolizumab combined with ipilimumab increased the survival by 50% (anti-CTL4 and anti
PD-1). However, there is always room for improvement.
Specific tumor rejection in mouse models are like the Sesamstreet of immunology in oncology. Main
player in this research are the dendritic and T-cells that start and adaptive response. In the bone
marrow progenitor cells can develop into B- and T-cells and NK-cells (but these are part of the innate
response). The B-cells activated will transform into plasma cells and T-cells will get activated. An
adaptive response will lead to an memory response! The primary response leads to recognition and
removal by T-cells to clear the infection and a secondary response will enhance to the memory
response (contraction phase). Some memory response will last for life.
Antibody-mediated tumor therapy: antibodies bind to tumor cells > NK-cells with Fc receptors (CD16)
are activated to kill to tumor cells. They can also be used by conjugating antibodies with a toxin and
when the antibodies bind to the tumor cell the conjugates will be internalized, killing the cell. This
same method can also be enhanced by conjugating antibodies with radioisotopes making the
radiation killing the tumor and neighbouring cells.
Cytotoxic T-cell recognizes complex of viral peptides with MHC-I and kills the infected cell. T-cell
forces the tumor cell to commit suicide by the secretion of granzymes. They can do this for
thousands of tumor cells.
Dendritic cell = professional antigen-presenting cells (APC) to activate T-cells. They
take up antigen, process them and present them. Macrophages, vacuum-cleaning
relatives of dendritic cells also take up antigens and induce homeostasis in the
tissue (M2 macrophages) = wound healing > stop an immune response. Tumor cells
found a way that macrophages will appear mostly as M2 which will help tumor
cells to grow and spread. Moreover, DCs and MQs can differentiate into each
other. Activated DCs moves to the lymph nodes to activate T-cells to become
,cytotoxic which can migrate through the vessel and extravasate into tumor tissue and kill tumor cells.
The cancer immune cycle points out how cells can evade this response.
1. Antigen presentation of tumor cells
2. DC gets activated
3. DC migrate to the lymph node for antigen presentation.
4. T-cell receptor recognise MHC complex (signal 1)
a. All cells carry MHC-I peptides in the ER which are
expressed after degraded viral/antigen
endogenous molecules > activated receptor
moves on the membrane
b. Exogenous antigens are neutralized by
endosomes and can fuse with lysosomes >
peptides are processed and bind to HLA-DM with
an higher affinity than CLIP and moved up the
membrane. CLIP makes sure that no other peptides bind to the receptor to prevent
activation.
c. There is also a phenomenon called cross presentation of exogenous antigen-derived
peptides in MHC-I molecules. This can happen by the vacuolar pathway or cytolytic
pathway.
5. T-cells also need co-stimulation (signal 2), fail/safe mechanism to prevent auto-immune
reactions. This is done by PD-1 and CTLA4 expression.
a. When there is no co-stimulation the T-cell will get shut down (anergy). Tumor cells
do this to switch-off T-cells.
6. Signal 3 occur by cytokines produced by the th1 activates T-cells and th2 activates B-cells.
The type of infection determines the type of dominant th-cell.
a. IL-12 activates th1 (inducing IFN-𝛾) > cellular immunity and clearance of intra-cellular
pathogens.
b. IL-4 activates th2 > humoral immunity, clearance of extracellular antigens and allergy
responses.
c. TGF-b activates T-reg cells > tolerance/immune suppression.
d. IL-6 activates th17 > tissue inflammation, autoimmunity, and clearance of
extracellular pathogens.
Hypoxic areas and tissue damage induce a release of cancer
signal antigens that activates DCs by damage associating
patterns (eats its surrounding to see if it needs to become
activated) > maturations is induced by cytokines, bacterial
ligands or viral ligands by Toll-like receptors (TLR). There are 6
types that can bind different components. When these
receptors bind they phosphorylate their tails > activate
signalling pathways and NF-kB > antiviral immune response, T-
cell stimulation or inflammation.
DCs activation is vital in vaccines because they can activate T-cell responses. Release of the antigens
can work stimulatory to DC differentiation and maturation. The more specific the immune response
will be to tumor cells, the less side effects will occur.
- Neoantigens derive from DNA mutations (Ras oncogene) or viral oncogenes (HPV) > are only
in tumor cells and are thus very specific.
, - Cancer testis antigen, semi-specific for cancer cells but you can find them in gonads (sperm
cells).
- Melanoma for instance, low specific tumor antigen
- Growth factor receptors are often upregulated, but are present on normal cells > can lead to
immune responses if you target them.
The 3 E’s indicating the 3 phases of tumor cells evading an immune response: elimination,
equilibrium (resistance against immune response begin to occur) and escape (immunosuppressive
cells survive and grow). So it is a Darwinian process and the immune cells are edited by the tumor
cells (= immune-editing). There are 11 ways in which tumor cells can evade our immune system.
When MHC-I is down-regulated the NK-cells takes over.
Tumor cells can secrete chemokines that attract T-reg cells that inhibit T-effector-cross and block DCs
to activate T-cells.
In immunotherapy you need to know differences between prophylactic and therapeutic and passive
against active. CAR-T therapy: antigen receptor binds antigen > signal MHC-I and II > activate T-cells.
Vaccination is an active therapy because the body need to induce the response. Autologous DC
vaccination: extract DC > mature + activate them with tumor elements > bring back in the body.
Main message
Main player in this research are the dendritic and T-cells that start and adaptive response. In the
bone marrow progenitor cells can develop into B- and T-cells and NK-cells (but these are part of the
innate response). The B-cells activated will transform into plasma cells and T-cells will get activated.
An adaptive response will lead to an memory response! The primary response leads to recognition
and removal by T-cells to clear the infection and a secondary response will enhance to the memory
response (contraction phase). Some memory response will last for life.
The Mellman cancer immunity cycle:
1. Release of tumor antigens
a. Toll-like receptors present the antigens for DC maturation
2. Tumor antigen presentation by DCs and migration to the lymph node
3. Priming and activating T-cells
a. Signal 1: Ag-MHC complex recognition + binding to TCR
b. Signal 2: Co-stimulation by PD-1 or CTLA4
i. No co-stimulation > T-cell anergy
c. Signal 3: Cytokine secretion for Th polarization
4. Trafficking of T-cells to the tumor
5. Infiltration of T-cells into tumors
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