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).
Evasion of Immune Response by Tumours: What is Concomitant Immunity?
‘Concomitant immunity’ is described as an immune rejection reaction occurring at one site, co-existing with the progressive growth of an antigenically identical tumour elsewhere in the organism.
What are Lymphoproliferative Disorders?
The normal response of immune cells to infection or inflammation is to undergo reactive polyclonal proliferation. Monoclonal expansion can give rise to leukaemia, lymphomas or myeloma. A clone of malignant cells (lymphoid, myeloid or monocytic) originating in the bone marrow is called a leukaemia. Malignant cells (blasts) may be seen in the peripheral blood.
A clone of malignant cells
originating in the bone marrow is called a ….
leukaemia
Could be lymphoid, myeloid or monocytic
Define Lymphomas
Lymphomas are tumours of lymphoid cells originating in the peripheral lymph tissues. These malignant cells may infiltrate the spleen, liver, brain, bone marrow and lungs. Leukaemia and lymphomas arise from a single cell
which has undergone malignant transformation leading to uncontrolled division into a clone of identical cells.
What is acute leukaemia?
Acute leukaemia is the clonal proliferation of haematopoietic cells that results in an excess of immature cells and leads to functional bone marrow failure.
Acute leukaemia is broadly classified as acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL).
Acute leukaemia is broadly classified as which two conditions?
acute myeloid leukaemia
(AML)
acute lymphoblastic leukaemia (ALL).
What is Chronic Myeloid Leukaemia?
Chronic myeloid leukaemia (CML) is a clonal disorder in which cells of the myeloid lineage undergo inappropriate clonal expansion. The disease progresses through three distinct phases – chronic phase, accelerated phase,
and blast crisis – during which the leukemic clone progressively loses its ability to differentiate.
What are the three phases of Chronic Myeloid Leukaemia?
The disease progresses through three distinct phases – chronic phase, accelerated phase, and blast crisis – during which the leukemic clone progressively loses its ability to differentiate.
In which phase of chronic myeloid leukaemia do patients most commonly present ?
CML presents in the chronic phase in about 90% of
patients. Many are asymptomatic and discovered incidentally. Common non-specific symptoms include fatigue, night sweats, weight loss, or spontaneous bruising or bleeding, splenomegaly, splenic infarction, anaemia, or platelet dysfunction.
Symptoms of Chronic Myeloid Leukaemia?
Many are asymptomatic and discovered incidentally. Common non-specific symptoms include fatigue, night sweats, weight loss, or spontaneous bruising or bleeding, splenomegaly, splenic infarction, anaemia, or platelet dysfunction.
What is Chronic lymphocytic leukaemia (CLL)?
lymphocytic Leukaemia - A clone of malignant cells
(in this case lymphoid) originating in the bone marrow
Chronic lymphocytic leukaemia (CLL) is the commonest leukaemia in the Western world. It is a disease of the elderly and is usually incurable except in a minority of patients suitable for allogeneic haematopoietic stem cell transplantation.
The lymphomas form a group of neoplasms in which the malignant cells derive from lymphocytes. When early progenitor B- or T-cells are involved, the patient presents with which type of lymphoma or leukaemia?
acute lymphoblastic leukaemia (ALL) or
lymphoblastic lymphoma.
The lymphomas form a group of neoplasms in which the malignant cells derive from lymphocytes. The final stage in B-cell maturation following antigen encounter leads to the production of memory cells and plasma cells,
the cancerous equivalent of which is…
myeloma.
How are lymphomas categorised as Hodgkins or non-Hodgkins?
Approximately 15% of lymphomas are termed Hodgkin’s
lymphomas (HL), identified on histopathological grounds. All other lymphomas are termed Non-Hodgkin’s lymphomas (NHL). They represent a highly heterogeneous group with around 40 entities (World Health Organization classification), although a few common types predominate
Is risk of developing Hodgkins or non-Hodgkins lymphoma increased in congenital and acquired
immunodeficiency states?
Workbook seems to be conflicting on this. pg. 86.
The risk of developing NHL is increased in congenital and acquired immunodeficiency states, including human immunodeficiency virus (HIV) infection, other immune disorders, such as rheumatoid arthritis, and post-transplantation.
Hodgkin’s - It is more frequently seen in other immunodeficient states, including post-organ transplant, immunosuppressive therapy and primary immunodeficiency states including autoimmune lymphoproliferative syndrome and ataxia telangiectasia.
Why might Various infectious agents be associated with lymphoma?
chronic antigenic stimulation forming one step in a multi-step carcinogenic process
What time of lymphoma is associated with epstein-Barr virus?
Epstein–Barr virus (EBV) is associated with Burkitt’s lymphoma, prevalent in malarial areas of sub-Saharan Africa but rare in developed countries, and is present in two-thirds of HIV related lymphomas.
List 3 viruses strongly associated with lymphomas
Epstein–Barr virus (EBV) is associated with Burkitt’s lymphoma,
Hepatitis C virus (HCV) infection increases the risk of non-Hodgkins lymphoma 2.5-fold.
Infection with human T-cell lymphoma virus 1 (HTLV1) causes a rare type of NHL (ATLL), but only in a small minority of chronic carriers.
There is a strong association between Helicobacter pylori and lymphomas of Mucosa-Associated Lymphoid Tissue (MALT) in the stomach.
Presentation of lymphomas
The most common presenting symptom is painless lymph node enlargement. Indolent lymphomas present with widespread, slowly progressive lymphadenopathy with few constitutional symptoms. Aggressive lymphomas present with rapidly enlarging lymph nodes and have associated constitutional (‘B’) symptoms (pyrexia, weight loss, night sweats).
Why are patients routinely tested for HIV and hepatitis before commencing treatment for lymphoma?
Patients are routinely tested for HIV, hepatitis B virus (HBV) and HCV before the commencement of immunosuppressive NHL treatment, which can
exacerbate these conditions
Three types of Burkitt’s Lymphoma
- Endemic BL
- Sporadic BL
- HIV-associated BL
What are group is most associated with Burkitt’s lymphoma?
Burkitt’s lymphoma (BL) is a highly aggressive disease of children and young adults.
In Endemic BL, the original disease described by Denis Burkitt, the peak incidence is between ages 4–7
How do children with endemic Burkitt’s Lymphoma present?
endemic regions in equatorial Africa and climatic factors. This region corresponds to that with endemic malaria. The peak incidence is between ages 4–7, and children typically present with rapidly enlarging tumours of the jaw or other facial bones. Extra-nodal involvement
is frequent, especially ovaries, kidneys and breasts Most tumours are EBV-associated.
How do children with Sporadic Burkitt’s Lymphoma present?
The most common presentation is with an abdominal mass, especially of the ileo-caecal region. As in endemic BL, other extra-nodal involvement is frequent, especially ovaries, kidneys and breasts
In what condition do most cases arise from the clonal proliferation of B lymphocytes and the majority of cases are curable?
Hodgkin Lymphoma
Presentation of Hodgkin Lymphoma
Presentation includes a painless lymph node
mass, often affecting the cervical chain although any nodal sites may be affected. Extra-nodal disease is less common and splenic or bone marrow involvement occurs only in the minority of cases. B symptoms (recurrent fevers, night sweats and loss of weight) affect a substantial proportion of cases.
Two subtypes of Hodgkin Lymphoma
The disease has two subtypes:
classical Hodgkin lymphoma
nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)
These are distinguished by their morphology and immune-phenotype and have certain clinical characteristics.
In classical Hodgkin lymphoma, the malignant cell is termed a
Reed–Sternberg (RS) cell
Reed–Sternberg (RS) cell
In classical Hodgkin lymphoma, the malignant cell is termed a Reed–Sternberg (RS) cell and is typically large with two (or more) nuclear lobes containing separate nucleoli often creating an ‘owl’s eyes’ appearance. Mononuclear forms are termed Hodgkin cells.
In classical Hodgkin lymphoma, the malignant cell is termed a Reed–Sternberg (RS) cell and is typically large with two (or more) nuclear lobes containing separate nucleoli often creating an ‘owl’s eyes’ appearance. Mononuclear forms are termed….
Hodgkin cells.
Describe the appearance of Reed–
Sternberg (RS) cells
typically large with two (or more) nuclear lobes
containing separate nucleoli often creating an ‘owl’s eyes’
the malignant cell in classical Hodgkin lymphoma
Describe the particular requirements of transfusion after Hodgkin lymphoma
Hodgkin lymphoma confers long-term immune dysregulation associated with a risk of transfusion-associated graft-versus-host disease. This leads to a lifelong requirement for the irradiation of cellular blood products, to inactivate the residual lymphocytes that can cause this complication if transfusion is required.
Myeloma
Myeloma is a clonal proliferation of bone marrow plasma cells that causes bone lesions, anaemia, renal failure and recurrent infections,
What is the name of the condition in which a clonal proliferation of bone marrow plasma cells that causes
bone lesions, anaemia, renal failure and recurrent infections?
Myeloma
Presenting features of Myeloma
Presenting features are variable and non-specific and include anaemia (normocytic normochromic), bone pain, (osteolytic deposits or fractures), fatigue, weight loss, renal impairment (tubular blockage by cast nephropathy, amyloid deposition, dehydration, sepsis or use of nephrotoxic drugs), hypercalcaemia, hyper-viscosity (Can lead to blurred vision, headache, confusion and bleeding from mucous membranes) and recurrent infection (from immune-paresis due to the reduction of uninvolved immunoglobulins).
Suggest mechanism through which monoclonal antibodies may be used to target cancer cells
Many are used as unconjugated ‘naked’ antibodies.
Once antibodies have bound to a tumour antigen it will activate an effector mechanism such as the complement system, opsonisation, or by serving as antagonists for cell surface receptors important for cell proliferation or angiogenesis (growth of blood vessels).
potential use of anti-tumour antibodies conjugated with
toxins (e.g. diphtheria toxin, or the plant toxin ricin), or highly radioactive isotopes, thus serving as targeting agents to deliver these toxic molecules to tumour cells.
Summarise Adoptive Cellular Therapies for Cancer
T lymphocytes are isolated from blood and grown in culture before being introduced back into the patient to act as part of the immune system. Lymphocytes removed from a tumour-bearing patient can be treated in vitro with lymphokines (e.g. IL-2), and the resulting ‘activated’ cells re-injected into the patient, in the hope that the tumour cells will be killed by tumourspecific killer T-cells present in the transfused cell population.
Chimeric Antigen Receptor Treatment for Cancer
Chimeric antigen receptors are genetically introduced into a patient’s T cells in a lab and then reintroduced into the patient as a form of therapy. Stimulation of Host Anti-Tumour Immune Response. Some strategies have
focused on promoting the immune responses against tumours or blocking inhibitory mechanisms that suppress anti-tumour immunity.
Immunological Treatment for Cancer: Vaccination
Vaccination have been created using patients own tumour antigens, or antigens produced by stimulating dendritic cells (Remember that some tumours caused by oncogenic viruses can be prevented by vaccination e.g. Hep B and HPV see infection unit).
Immunological Treatment for Cancer: Checkpoint Blockade
Blocking the inhibitory signals that control lymphocytes allows a more active host immune response
Inhibit tumor-induced suppression of T-cell activation or function
Antibodies target immune checkpoints to enhance antitumor response
e.g. CTLA-4 and PD1 (programmed death 1)
Immunological Treatment for Cancer: Cytokine Therapies
Cytokine have the ability to promote lymphocyte activity, however there can also be some severe toxic side effects.
•Proteins that are naturally secreted by immune system cells
•Mechanism of action
–Interleukin-2 (IL-2) stimulates T-cell proliferation
Define NEOPLASM
Abnormal growth of cells which persists after initiating stimulus has been removed
•Cell growth has escaped from normal regulatory mechanisms
4 stages of cell cycle
G1 - Growth
S - DNA Synthesis
G2 - growth and preparation for mitosis
M - mitosis (cell division)
What evidence do we have of the Role of the immune system in Cancer?
Examples:
- Malignant tumors develop up to 20 fold more in individuals with compromised immune systems
- T-cell infiltration within tumors predicts overall survival (OS) in multiple cancer types including bladder cancer
Two types of tumour specific antigens
Chemically induced - Tumour-Specific Transplantation Antigens, or TSTA.
virally induced - Tumour-Associated Transplantation Antigens (TATA).
Two examples of Tumour associated antigens
- oncofetal tumour antigens (inappropriate expression of embryonic gene)
- oncogene proteins
All tumour antigens will be presented on what structure?
MHC I
Tumour antigens will be presented on MHC I, which when bound to TCR, the CTL released what products?
Granzymes
Perforins
FAS-L
What is an Oncovirus?
When a virus infects a cell, it expresses proteins that cause the cell to proliferate and/or block apoptosis
The role of CD16 in antibody-dependent cell-mediated cytotoxicity (ADCC)
- Many cells involved in the innate immune responsealso express CD16 (Fc receptor), which is a low affinity receptor forimmunoglobulins such as IgG.
- Immunoglobulin binding by CD16 targets innate immune cells to the immunonglobulin-bound target cell, and triggers target cell destruction.
Immune system and cancer interact in a dynamic process, known as the 3 E’s. What are the 3 E’s?
Elimination (immune system eradicates cancer cells)
Equilibrium (immune system controls cancer outgrowth)
Escape (cancer overwhelms the immune system)
Tumour related mechanisms of escape (from immune surveillance)
Failure of tumour to provide a suitable antigenic target or an effective immune response.
- lack of recognisable tumour antigen
- lack of MHC 1
- deficit antigen processing
- antigen modulation
- antigenic masking of tumour
- resistance of tumour to tumoricidal pathways
- lack of co-stimulatory signals
- production of inhibitory cytokines
- shedding of tumour antigens
House related mechanisms of escape (from immune surveillance)
Failure of host to recognise antigenic tumour cells.
- immuno-suppresion or immunodeficiency
- deficiency in inducing apoptosis and cell death signalling
- infections or old age
- deficiency in tumour antigen presentation by host APC
- failure of host effector cells to reach the tumour (e.g. stroll barrier)
- failure of host to kill variant tumour cells
- T reg hindrance to tumour immunity
Cancerous illness of white blood cells is called…
Leukaemia
In leukaemia, white cells, instead of growing and developing normally, the white blood cells grow out of control but do not mature, which means they do not work properly.
- acute myeloid leukaemia (AML),
- acute lymphoblastic leukaemia (ALL),
Are both derived from which progenitor cell?
both hematopoietic stem cells
- acute myeloid leukaemia (AML) -> myeloid progenitor cell
- acute lymphoblastic leukaemia (ALL) -> lymphoid progenitor cell
What disease is Characterized by the abnormal proliferation B or T cells in lymphoid tissue causing lymphadenopathy?
Lymphoma
Which type of lymphoma mainly affects adults; the risk increases with age?
Non-Hodgkin lymphoma
Which type of lymphoma often affects young adults, most of whom can be cured, especially if diagnosed at an early stage?
Hodgkin lymphoma
Coley toxins.
In late 1800s Dr William Coley first noted that getting an infection after surgery seemed to help some cancer patients. he began treating cancer patients by infecting them with certain kinds of bacteria, which came to be known asColey toxins.
Cancer immunotherapy: Features of an Effective Immune Response
- Specificity - Ability to recognize and mount a specific response to distinct antigens
- Trafficking - Ability of activated immune system cells to migrate to particular antigens throughout the body
- Adaptability - Allows for a broader immune response (eg, immune response to additional antigens)
- Target elimination - Ability of immune cells to destroy their target (eg, cancer cells)
- Durability (immune memory) - Ability of immune system to recognize an antigen to which it has previously been exposed and provide long-lasting protection against it
Features of an Effective Immune Response: examples of specificity
- Seasonal flu mutates surface antigens
* Annual vaccination allows the immune system to effectively recognize and target the specific flu strain
Features of an Effective Immune Response: examples of trafficking
- Following exposure to activated APCs, naive T cells become activated
- Activated T cells are mobilized to areas containing antigen
4 main types of immunotherapy now being used to treat cancer
- Monoclonal antibodies (naked or conjugated)
- Immune Checkpoint inhibitors
- Therapeutic vaccines
- Other non specific immunotherapies (cytokines, interleukins etc)
Active vs passive cancer immunotherapy
Active:
- engaged immune system,
- durable
- e.g. therapeutic cancer vaccines
Passive
- enhanced pre-existing immune response
- short lived
- examples: mABs, cytokines
Very basic definition of Monoclonal Antibodies (mABs)
Proteins designed to bind to specific substances in the body
What type of drug is Herceptin?
naked monoclonal antibody used in treatment of HER2 positive breast cancer.
What is the function of HER2 receptors in breast cancer cells?
HER2 receptors send signals telling cells to grow and divide
HER2+ breast cancer cells - too many HER2 receptors send more signals, causing cells to grow too quickly
Herceptin (monoclonal antibody) may step the HER2 receptors from signalling the cell to grow
