Week 5: Tumor Immunology Flashcards
Define the term proto-oncogene
Normal genes that initiate or maintain cell division that may become cancer
genes
Lymph nodes are part of the peripheral lymphoid tissue, name two other examples
Lymph nodes, spleen, mucosal and cutaneous immune system
Where are T and B lymphocytes located in lymph nodes, and how is their anatomic separation maintained?
B lymphocytes reside in follicles in peripheral (secondary) lymphoid organs.
T cells reside in the parafollicular cortex of lymph nodes. B and T cells are
maintained in these locations by specific cytokines called chemokines, which
are secreted by stromal cells in the follicle and the parafollicular cortex,
respectively.
What are the main two main classifications of tumour antigens that the immune system reacts against?
Tumours express many mutated proteins that may appear foreign to the immune system and induce immune responses. Tumours may overexpress or inappropriately express antigens that are normally expressed only at low
levels in normal tissues or only during development and therefore do not induce tolerance. Some tumours caused by oncogenic viruses may express viral antigens that induce immune responses. They can be considered:
Products of Mutated Oncogenes and Tumour Suppressor Genes
Products of Other Mutated Genes Overexpressed or Aberrantly Expressed Cellular Proteins
· Tumour Antigens Produced by Oncogenic Viruses
· Oncofetal Antigens
· Altered Cell Surface Glycolipids and Glycoproteins
· Cell Type-Specific Differentiation Antigens
How do naive CD8+ T cells recognize tumour antigens, and how are these cells activated to differentiate into effector CTLs?
Naive CD8+ T cells recognize tumour antigens in the same way they recognize microbial antigens: by T cell receptor (TCR) binding to tumourderived peptides displayed on class I MHC molecules on dendritic cells. This means the DC must internalize tumour cells (or their products) and process the internalized tumour proteins by the class I MHC pathway, which involves proteasomal degradation of the proteins into peptides. The presentation of peptides derived from internalized proteins on class I MHC molecules is called cross-presentation. The DC displays not only tumour-derived peptide antigens to naive CD8+ T cells but also costimulators. The combination of antigen and costimulators activates clonal expansion and differentiation of the naive CD8+ T cells into effector cytotoxic T lymphocytes.
What risk factors are associated with malignant melanoma?
UV exposure and sun burn, number of moles,
skin type, previous melanomas previous SCC or BCC,
first-degree relative diagnosed with melanoma
Compromised immune systems as the result of chemotherapy, an organ transplant, excessive sun exposure, and diseases such as HIV/AIDS or lymphoma can increase your risk of melanoma.
What is the difference between grade of tumour and staging of a tumour?
Grading refers to the differentiation of the tumour with respect to the tissue from which it originates. Staging refers to the extent to which the tumour has spread and takes into account: the local extent of the tumour (T status), lymph node metastasis (N status) and distant organ metastasis (M status).
What, in general terms, are immunotherapies for cancer?
Therapies that harness the innate functions of the immune system
What are the 6 functional domains of antibody structure
- F ab region
- F c region
- heavy chain with one variable (Vh) domain followed by a constant domain, a hinge region, and two more constant domains
- light chain with one variable and one constant
- antigen binding site
- hinge region
What tracer is typically used in oncology PET
scans to add contrast to the images? Why would cancer cells take up more of this tracer?
FDG (fluorodeoxyglucose)
This tracer is a glucose analog that is taken up by glucose-using cells and phosphorylated by hexokinase (whose mitochondrial form is greatly elevated in rapidly growing malignant tumours).
Opioids given as pain control go through first pass metabolism.
What does this mean and how can this be avoided
First pass metabolism is where blood from the gut reaches the liver by the portal system, where the liver could metabolise the drug before it gets to the
systemic circulation. It can be avoided by parenteral route and sublingual or rectal route of administration.
Explain how tachyphylaxis can occur in the chronic treatment of patients with opiates.
Repeated use of an opioid causes mu receptors to become down-regulated and tachyphylaxis to occur requiring more opioid required to elicit same response.
You are working in a GP practice. Mr Grant a 70 year old man has recently been diagnosed with lung cancer. He has booked an appointment with you as he has some questions about his new diagnosis.
Mr Grant says he has read that the body’s immune system can fight off cancer. He asks why this hasn’t happened with him, and why he has a tumour on the lung. You explain that tumours are a bit like a parasite,
and they have mechanisms to prevent them from being eliminated from the host (you). What are some of these mechanisms?
· Weak antigenicity · Immunosuppression and tolerance induction · Release soluble antigens · Antigen-antibody complexes · Antigenic variation
Name two types of genes that can be affected by mutations and result in unregulated cell growth
· Oncogene
· Tumour suppressor gene
You are working in a GP practice. Mr Grant a 70 year old man has recently been diagnosed with lung cancer. He has booked an appointment with you as he has some questions about his new diagnosis. Mr Grant asks what factors can result in mutations that lead to tumours. You explain that mutations can result from inherited factors
or from exposure to chemicals in the environment- give some examples of each of these:
Inherited:
· Breast cancer BRCA1 and BRCA2 genes
· Bowel cancer
o Familial adenomatous polyposis (FAP)caused by a
fault in the APC gene
o Peutz Jeghers syndrome (PJS) linked to a gene fault called STK11
· Melanoma CDKN2A gene
Exposure to chemicals in the environment · Asbestos mesothelioma · Aniline dyes and bladder transitional cell cancer (TCC) · Smoking lung cancer · Sun- skin cancer
As smoking is associated with lung cancer and sun exposure is associated with skin cancer, which cancers are associated with asbestos exposure?
mesotheliomas
As smoking is associated with lung cancer and sun exposure is associated with skin cancer, exposure to which occupational chemical is associated with bladder transitional cell cancer?
Aniline dyes and bladder transitional cell cancer (TCC)
How are natural killer cells unique compared to other cells in the immune system with regards to the types of cells they are able to recognise?
NK cells are able to recognise cells that do not express MHC molecules. This is useful as many tumours do not express MHC molecules, which helps them to evade the immune system response.
When macrophages and natural killer cells are activated against tumours they can cause cytostasis and/or cytolysis. What do these terms mean?
· Cytostasis: inhibition of cell growth and multiplication, preventing growth of the tumour
· Cytolysis: dissolution or disruption of cells, effectively killing the tumour
Two non-specific immunotherapies that have been used for cancer are BCG and coleys toxin. How are these thought to work?
By activating macrophages, NK cells, cytokines that then attack tumours.
Imagine that you have been given the task to make a
drug to target and destroy tumour cells using immunotherapy. What could your drug target and what would it do?
Diagram: cytokines activate NKC and macrophages, which target tumour cells.
You could create a drug that results in activation of cytokines: these activate NK cells and macrophages which can target the tumour cell. You could create an antibody that would target the tumour cell – once you
have an antibody that targets tumour cells you could couple it with a cytotoxic drug- this would mean that cytotoxic drugs would be in high levels around the tumour, and lower concentrations in other areas of the body, this would reduce the side effects of cytotoxic drugs.
You could create a drug that would reduce the regulatory mechanisms that limit immune response- this would result in a more effective immune response to tumours
Mr Grant says he had a friend who was diagnosed with bowel cancer after having a blood test. He asks how that is possible. How would you explain this?
You explain that tumours can produce antigens, that if present in high levels in the blood can indicate a certain type of tumour cell is present and producing these antigens. These antigens are also known as tumour markers.
What cancers are linked with the following tumour markers?
CEA
CA125
CA 19-9
CEA - colon cancer
CA125 - ovarian cancer
CA 19-9 - pancreatic cancer
What tumour markers are linked with the following cancers?
- colon cancer
- ovarian cancer
- pancreatic cancer
CEA - colon cancer
CA125 - ovarian cancer
CA 19-9 - pancreatic cancer
Name five cancers that have been firmly linked to viruses, and name the viruses they are linked to:
· Burkitts lymphoma and nasophryngeal carcinoma- EBV
· Karposi’s sarcoma KSHV
· Hepatocarcinoma HBV
· Cervical cancer - papillomavirus
Cancer occurs when the DNA sequence within a gene is altered in such a way that the gene can no longer instruct the cell in which it resides to produce the normal version of the protein it encodes.
What are the three major factors are
known to initiate tumour development:
Chemical carcinogens: Many natural as well as man-made compounds
Ionising radiation
Viruses
Regardless of how tumour development is initiated, the consequence is:
Uncontrolled growth, resulting either from the abnormally high
expression of genes which stimulate cell proliferation (ONCOGENES)
Defective expression of genes which normally control proliferation
(Tumour Suppressor Genes)
Defective respond to apoptosis mechanisms
The theory of immune surveillance suggested that which division of the immune system destroy newly appearing neoplastic cells?
The theory of immune surveillance suggested that the adaptive immune system, particularly cell-mediate immunity (CMI), destroy newly appearing neoplastic cells as a result of the new antigens they tend to express.
True or false?
Many tumours can be shown to express cell surface antigens which are not expressed in the normal progenitor cells before the neoplastic transformation event.
True
If the immune system is able to detect tumours then tumours must express antigens that the body detects as non-self-antigens.
Many tumours can be shown to express cell surface antigens which are not expressed in the normal
progenitor cells before the neoplastic transformation event.
These antigens have been categorized based on their nature and distribution into which categories?
•Tumour specific Antigens
> chemically induced
> virally induced
•Tumour associated antigens
> oncofetal tumour antigens
> oncogene proteins
Tumour-Specific Transplantation Antigens, or TSTA. chemical or radiation induced tumours express a unique neo-antigen, different from other tumours induced by the same or different agent.
Tumour-Associated Transplantation Antigens (TATA). Tumours induced by oncogenic virus express virally encoded membrane antigens
Onco-fetal antigens: antigens are selectively expressed on tumours, but are also shared with some normal foetal or embryonic tissues. Thought to reflect their reversion to a less fully differentiated state.
Some tumour antigens are oncogene proteins.
What are Tumour-Specific Transplantation Antigens, or TSTA?
Tumor antigens that are products of diverse mutated genes. Generally chemical or radiation induced tumours express a unique neo-antigen, different from other
tumours induced by the same or different agent. These have been termed Tumour-Specific Transplantation Antigens, or TSTA.
What are Tumour-Associated Transplantation
Antigens (TATA)?
Tumours induced by oncogenic virus express virally encoded membrane antigens, termed Tumour-Associated Transplantation Antigens (TATA).
What is the difference between Tumour-Specific Transplantation Antigens (TSTA) and Tumour-Associated Transplantation
Antigens (TATA)?
Generally chemical or radiationinduced
tumours express a unique neo-antigen, different from other tumours induced by the same or different agent. These have been termed Tumour-Specific Transplantation Antigens, or TSTA.
Tumours induced by oncogenic virus express virally encoded membrane antigens, termed Tumour-Associated Transplantation Antigens (TATA).
What are Onco-fetal antigens?
Onco-fetal antigens: These antigens are selectively expressed on tumours, but are also shared with some normal foetal or embryonic tissues. Expression of such antigens by tumours is thought to reflect their reversion to a less fully differentiated state.
Once the body has recognised a tumour antigen it must try and destroy that cell. This is principally achieved by which cell types?
APCs ingest tumour cells and present the antigens on T cells.
CTLs specifically against the tumour antigens.
PROCESS: APCs ingest tumour cells and present the antigens on T cells. Given that tumours occur in nucleated cells they are normally presented on Class I MHCs. Once naïve CD8+ T cells have differentiated into effector CTLs complex signalling cascade results in them releasing granzymes and perorins FAS and FABL that all assist in the destruction of tumour cells.
Once the body has recognised a tumour antigen it must try and destroy that cell.
Describe this process.
APCs ingest tumour cells and present the antigens on T cells. Given that tumours occur in nucleated cells they are normally presented on Class I MHCs. Once naïve CD8+ T cells have differentiated into effector CTLs complex signalling cascade results in them releasing granzymes and perorins FAS and FABL that all assist in the destruction of tumour cells.
List the name of 4 processes by which tumours evade the immune system
Tolerance Immunomodulation Immunoselection Enhancing Antibodies Immuno-stimulation Blocking Factors Immuno-suppression Concomitant Immunity
Evasion of Immune Response by Tumours: What is Tolerance?
A state of immunological tolerance may be promoted by the presence of very high levels of tumours antigens, particularly soluble forms which may be shed into the serum by tumour cells.
Evasion of Immune Response by Tumours: What is Immunomodulation?
Antibody binding to a membrane antigen on either normal or neoplastic cells may result in the disappearance of that antigen from the cell surface either by endocytosis or by shedding. Once a tumour cell has lost its neoantigen, it becomes invisible to the immune system.
Evasion of Immune Response by Tumours: What is Immunoselection?
Variant cells can appear in a tumour population which have lost a particular antigen through a mutational event; such a variant will have a selective advantage in the face of an even slightly effective immune response, and
cells with the antigen-negative phenotype will therefore tend to progressively take over the population.
Evasion of Immune Response by Tumours: What is Antibodies Enhancement?
Most nucleated cells are relatively resistant to complement-mediated lysis, and destruction of grafted tissue is largely the role of cell-mediated immunity. However, if antibodies are present which can bind to neoantigens, they may effectively “hide” these antigens which might otherwise serve as targets for T-cell-mediated killing, and thus “enhance” the survival of such cells.
Evasion of Immune Response by Tumours: What is Immuno-stimulation?
Antibodies binding to tumour cells may also, in some cases, actually stimulate cell growth, through the generation of receptor mediated proliferative signals.
Evasion of Immune Response by Tumours: What are Blocking Factors?
Soluble factors in the serum of tumour patients which can inhibit an existing immune response from affecting the tumour. The best characterised “blocking factors” have turned out to consist of circulating antigen-antibody
complexes containing tumour antigens, which may blind or divert the immune response in ways which are still poorly understood.
Evasion of Immune Response by Tumours: What is Immuno-suppression?
Tumour- patients often exhibit a substantial degree of generalised immunosuppression, resulting directly or indirectly from inhibitory cytokines and other substances secreted by the tumour (e.g. Hodgkin’s lymphoma).
