Module 5 Flashcards
(213 cards)
1
Q
ELISA (enzyme-linked immunosorbent assay)
A
broadly applicable technique that can be modified to detect and quantify substances such as peptides, proteins, antibodies, hormones, and other molecules
- based on antigen-antibody interaction so its very specific
2
Q
flow cytometry
A
method of detecting and quantifying different cell types in a mixed cell suspension
3
Q
monoclonal antibodies
A
production of monoclonal antibodies is a technique that was developed by George kholer and cesar Milstein in 1975
- antibodies produced by a single clone of a B-cell that are specific for a single epitope
4
Q
how does the ELISA work -step 1
A
the bottom of the wells are coated with an antigen that is specifically recognized by antibody you wish to measure (primary antibody)
5
Q
how does the ELISA work -step 2
A
wells are washed to remove any excess antigen not attached to bottom of well
6
Q
how does the ELISA work -step 3
A
sample containing the antibody to be measured is added to well – the primary antibodies if present, will bind to the antigen attached to bottom of well
7
Q
how does the ELISA work -step 4
A
wells are washed again
8
Q
how does the ELISA work -step 5
A
an enzyme-conjugated secondary antibody is added to the well, this will bind to Fc portion of primary antibodies
- the secondary antibody recognizes antibodies from a particular animal (anti-human, etc)
9
Q
how does the ELISA work -step 6
A
wells are washed again
10
Q
how does the ELISA work -step 7
A
substrate of the enzyme attached to secondary antibody is added to well
- the reaction of substrate (chromogen) and enzyme produces a coloured product which can be measured by absorbance
11
Q
enzyme-conjugated secondary antibody
A
a secondary antibody specifically binds to primary antibody
12
Q
chromogen
A
substance that can be readily converted into a dye or other coloured compound
13
Q
what does the ELISA measure?
A
- measures a coloured reaction product by absorbance with the help of a machine called a spectrophotometric plate reader
- data measured correlates with presence of an antibody or antigen
- information can be used to detect the presence of a viral disease
14
Q
indirect ELISA
A
detects or quantifies antibody (levels of antibodies that are present)
15
Q
example of the indirect ELISA
A
used to determine the presence of serum antibodies against HIV
16
Q
detection
A
only confirms the presence or absence of a substance
17
Q
quantification
A
evaluates the concentration
- Requires a standard curve
18
Q
standard curve
A
measurement of absorbance of known concentrations of the substance
19
Q
sample concentration
A
can be determined by comparing the measured absorbance of the sample against the absorbance of the standard curve
20
Q
sandwich ELISA
A
detects or quantifies an antigen
21
Q
how does the flow cytometry work - step 1
A
- narrow stream of cells in a single file is passed through a laser light source
- the way laser light is scattered is unique to each cell type
22
Q
what does measuring FCS do?
A
allows for discrimination of cells by size
23
Q
FCS intensity
A
proportional to diameter of the cell
24
Q
SSC (sample stained cells)
A
provides information about internal complexity of a cell
25
other way flow cytometry can be used
used to determine the proportion of cells expressing a particular antigen
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how can FC be used to determine the proportion of cells expressing a particular antigen?
1. cells are labelled with a specific antibody
2. the antibody is coupled with a fluorescent marker (or “stained”)
3. this fluorescent marker can be excited by a light of a specific wavelength
4. the fluorescent marker emits a light with a characteristic different wavelength
5. only cells expressing the antibody in question will emit light of this specific wavelength
27
what does flow cytometry measure?
measures physical properties of a cell + used to determine complete blood counts (CBC)
- also used to detect specific antigens on or inside a cell
- measures size, shape, and granularity to identify distinct cell types in a mixed cell suspension
28
What can be readily determined due to each cell in a mixed suspension being assessed?
1. total number of cells in the suspension
2. number of cells of a particular type in the suspension
3. overall composition of the suspension
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Clinical Application of Flow Cytometry
1. can be used to diagnose cancer in a variety of ways
2. main diagnostic tests focus on detecting DNA aneuploidy, analyzing cell cycles and the immunophenotypical characterization
30
example of flow cytometry measure?
diagnosis of AIDS is made based upon the number of CD4+ T-cells found a patients serum (below 200 cells/mm2)
- FC used to identify and count these specific T-cells in a blood sample
31
how do monoclonal antibodies work?
produced in labs by hybridomas, immortal cells that produce unlimited quantities of one identical antibody
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hybridomas
result of fusion between a plasma cell and a cancerous cell
(myeloma)
- share properties of both plasma cells and myeloma cells
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myeloma cells
immortal growth = divides indefinitely
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plasma cell
produce specific antibodies against on antigen
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hybridoma cell
a perpetual source of antibodies against one antigen
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what do monoclonal antibodies measure?
not a specific technique of measurement, rather is a tool useful in many applications
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clinical applications
1. immunotoxins and radiolabelled antibodies
2. can be produced for defence against specific diseases and even cancer
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immunotoxins
consists of a tumour-specific monoclonal antibody attached to a deadly toxin
- used to target and eliminate tumour cells and treat cancer
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radiolabelled antibodies
monoclonal antibodies tagged with a radioactive isotope can be used to diagnose tumours earlier than other methods
- can bind to antigens on a tumour thereby allowing the precise location of a tumour within the body to be visualized
40
why are monoclonal antibodies better than polyclonal antibodies?
they are a homogenous population of antibodies with exquisite specifically for a single antigen whereas polyclonals could recognize multiple antigens
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what are vaccines made up of?
fragments of the pathogen or the entire pathogen that is modified (killed or attenuated), allowing the IR to develop without counteracting the disease
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what does vaccination allow?
IS the opportunity for "target practice"
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vaccine
type of biological preparation which provides active artificial immunity to a particular disease-causing agent
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what is the type of vaccine largely dependent on?
nature of disease-causing agent and how the IS recognizes and responds to infection
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4 types of vaccine
1. Live-attenuated vaccine
2. Killed-inactivated vaccine
3. Toxoid vaccine
4. Subunit vaccine
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live attentuated vaccine characteristics
contains a modified strain of the disease-causing agent which has lost its pathogenic ability, but retains its capacity to replicate within the host
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advantages of live attentuated vaccine
1. provides prolonged exposure to disease-causing agent
2. is suitable to generate cell-mediated immunity
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disadvantages to live attentuated vaccine
1. potential to revert to a virulent form
2. requires a specific storage and transport conditions (ex. Refrigeration)
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examples of live attentuated vaccine
1. smallpox vaccine
2. oral poliovirus vaccine (sabin)
3. measles vaccine
50
killed-inactivated vaccine characteristics
1. contains a strain to the disease-causing agent that has been inactivated by heat, chemicals or radiation
2. has the ability to generate IR, but is unable to replicate
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advantages to killed-inactivated vaccine
1. safer option as it cannot mutate back to virulent form
2. easy to store and transport
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disadvantages to killed-inactivated vaccine
1. generally requires multiple booster doses to maintain immunity
2. generally must be administered by injection
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examples of killed-inactivated vaccine
1. Rabies vaccine
2. Flu (influenza) vaccine
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booster doses
extra administration of a vaccine after a primary dose has been given
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toxoid vaccine characteristics
contains an inactivated toxin which is a product from the pathogen that is causing the disease
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advantages of the toxoid vaccine
1. safe as it is not a living organism that can divide, spread and/or revert
2. stable as they are less susceptible to changes in temperature, humidity and light
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disadvantages of the toxoid vaccine
may require several doses and usually need an adjuvant
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examples of the toxoid vaccine
1. tetanus vaccine
2. diphtheria vaccine
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adjuvant
a substance that enhances the body’s IR to an antigen
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subunit vaccine characteristics
contains only a small part or fragment of the disease-causing agent
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advantages of the subunit vaccine
safest type of vaccine – can be used on everyone, including immunocompromised pregnant and elderly populations
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disadvantages of the subunit vaccine
rarely successful at inducing long-lasting immunity, which means it will require multiple booster doses to maintain immunity and might even need to be conjugated to a carrier
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example of the subunit vaccine
hepatitis B vaccine
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carrier
a stronger antigen than the desired target antigen
- by covalently attaching a strong antigen to a poor antigen, the overall immunological response is strengthened and hopefully the immunological response to the poor antigen is also improved
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what are mRNA vaccines used for?
known for their use against SARS-CoV-2
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what is mRNA used for?
used in several formulations to fight the virus (ex. Bivalent vaccine, boosters, etc.)
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what are formulations of mRNA vaccine being used to investigate?
1. other infectious diseases (HIV, influenza)
2. non-infectious clinical conditions (pancreatic cancer, heart tissue regeneration)
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what does the principle of assay rely on?
1. relies on use of mRNA to produce viral proteins and recruit immune cells to respond to antigenic target
2. these proteins are then displayed on cell surface of an APC to induce B-cells (antibodes) and T-cell immunity
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SARS-CoV-2
virus that caused COVID-19
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mRNA vaccine for COVID-19
uses lab-made SARS-CoV-2 messenger RNA 9mRNA) to trigger an IR
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RNA and DNA-based vaccines
involve making genetic material only they do not require the use of a whole virus
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mechanism for mRNA virus steps
1. vaccine production
2. host cell
3. APC
4. IR
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vaccine production
1. mRNA is made in lab from a DNA template of the virus
2. mRNA encodes an antigen of the virus
3. for COVID-19 the mRNA encodes the spike proteins on surface of the virus
4. mRNA is incorporated into a formulation that can administered as a vaccine
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host cell
once inside the body, the mRNA entered the host cell and uses host cell machinery to produce the spike protein
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APC
1. newly formed spike proteins exits the cell and is recognized by an APC
2. APC internalizes the spike protein and processes it into a peptide (or antigen)
3. APC then displays the antigen on the surface of cell via MHC
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immune response
1. antigen is recognized by a T-helper cell which initiated an IR
2. B-cells produce antibodies that stop the virus from infecting cells
3. T-cells destroys cells infected with the virus
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antivirals medication against COVID-19
1. antiviral medication can treat COVID-19 once being infected
2. does not prevent COVID-19 - only treats
3. taken orally
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2 main antiviral medications
1. polymerase inhibitor
2. protease inhibitor
79
polymerase
enzyme that plays a central role in viral replication and transcription
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polymerase inhibitor used to treat COVID-10
Molnupiravir
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polymerase inhibitor function
increases frequency of viral RNA mutations and impairs replication of virus
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proteases
1. cut proteins into smaller, more workable pieces
2. often administered in combination
3. since these drugs disrupt the assembly of the virus, they cant replicate and infect other cells
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types of protease inhibitor
1. Nirmatrelvir
2. Ritonavir
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Nirmatrelvir
stops protease from cutting viral proteins into functional pieces
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Ritonavir
protects nirmatrelvir from destruction by the body and allows it to keep working
86
evolution of vaccines
1. recognized by the British Medical Journal as one of the greatest medical advances in history
2. Dr. Edward Jenner’s use of extracts prepared from cowpox lesions as a means of protecting his patients against smallpox infection
3. jenner’s discovery of using vaccination for protection against a viral disease came nearly 100 years prior to the discovery of viruses by Dmitry Ivanovsky in 1982
87
HPV
causes cervical cancer and genital warts
- in 2002 a clinical trial demonstrated that a virus like particle (VLP) vaccine could protect against infection by a type of HPV often associated with cervical cancer
- efficacy was 100%
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VLP
composed of the structural proteins of HPV, which can self-assemble into particles that resemble the natural virus both structurally and immunologically
89
are VLP infectious
do not contain viral DNA
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3 HPV vaccines
1. Cervarix
2. Gardasil
3. Gardasil 9 (protects against 9 types)
91
ebola virus (EBOV) and marburg virus (MARV)
part of the filoviridae family of viruses that case hemorrhagic fever with high mortality rates in humans and nonhuman primates
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what do EBOV and MARV produce?
transmembrane glycoproteins (GPs) though to play a role in the virulence of these viruses
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mice with EBOV and MARV GPs
the mice became protected against infection from the live virus
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vaccine using GPs from EBOV
put GPs from EBOV into a live attenuated recombinant vesicular stomatitis virus (VSV) that expresses the transmembrane GPs of EBOV and MARV
- vaccine prevented spread of EBOV in 2018
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genital herpes
1. caused by infection with herpes simplex virus (HSV) types 1 or 2
2. infections are permanent, requiring lifelong management
3. pose a serious health threat to newborns through vertical transfer
4. cause significant emotional distress in infected individuals
5. increase susceptibility to and spread of HIV infection
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genital herpes vaccine
subunit vaccine
- composed of a prominent structural protein of HSV-2 (type most associated with genital infections)
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genital herpes vaccine efficacy
1. vaccine showed promise in early clinical trials
- effiacy of >70% in women who were seronegative for noth HSV-1 and HSV-2 at beginning of trial
2. larger trial involving 8323 seronegative women showed much lower efficacy (20%) and no protection from HSV-2
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what does failure of genital herpes vaccine cause?
considering developing a live attenuated vaccine
99
vertical transfer
passage of a disease-causing agent from mother to baby during the period immediately before and after birth
100
seronegative
giving a negative result for a test of blood serum for presence of host antibody response against a foreign particle/pathogen
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what 3 things does seronegative inform you of?
1. IgG vs. IgM levels – indicate when host was exposed to pathogen
2. If the host has even been exposed to a pathogen
3. If the host has been vaccinated
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phases of vaccine development
1. lab studies
2. preclinical studies
3. clinical trial phase I
4. clinical trial phase II
5. clinical trial phase II
6. health canada approval
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step 1 - lab studies - vaccine development
1. identify the infectious agent causing disease and select a strain (or subtype) relevant to the target population used to produce the vaccine
2. largely depends on research from lab via assays
3. involves developing and testing manufacturing process of vaccine according to good manufacturing practice standards
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step 2 - preclinical studies - vaccine development
1. involve research carried out in animal models
2 occurs before clinical trials begin
3. researchers carry out challenge studies to demonstrate the immunogenicity of the vaccine in animal models
4. carries out safety studies to evaluate possible toxicity of vaccine which would prevent its use on humans
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which stage evaluates possible toxicity?
preclinical studies
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what does clinical development involve for vaccines?
3 phases
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3 phases of clinical vaccine development?
1. clinical trial phase I
2. clinical trial phase II
3. clinical trial phase III
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clinical trial phase I
1. involve small trials (10-<100 people) to assess vaccine safety by evaluating local and systemic reactions after administration
2. provides data on immunogenicity of vaccine and IR it evokes
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clinical trial phase II
1. occurs at a bigger scale (50-500 people) to collect data on safety, side-effects and efficacy of vaccine
2. evaluates dosage requirement and vaccination schedule (ex. need for booster) in target populations
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clinical trial phase III
1. involve multiple geographic sites with many hundreds of subjects (300 - 30,000 people) to evaluate efficacy under natural disease conditions
2. must complete safety assessment
3. if successful in retaining safety and efficacy, requires license to market for human use
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heath canada
regulatory authority in Canada responsible for ensuring the quality, safety and efficacy of all biologic drugs, including vaccines for human use
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health canada and vaccine
vaccine candidates must be submitted to HC to be considered for approval with sufficient scientific and clinical evidence to show its safe, efficacious and of suitable quality
- vaccines cannot be used clinically without approval from HC
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why is vaccine regulation necessary?
they are usually given to very large numbers of healthy individuals
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vaccination in canada
1. routine in canada
2. responsible for a dramatic decline in vaccine-preventable disease incidence over the years
3. free of charge for eligible individuals through respective provincial immunization program
4. confer protection against a wide range of diseases
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vaccine trends in canada
number of cases has significantly dropped for multiple diseases when vaccine is induced
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challenges with the vaccine development
1. cost
2. the cold chain
3. continuous monitoring
4. the gold standard
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cost of vaccine development
high cost of development of vaccines sometime leads to premature abandonment of clinical research, especially if the disease threat is restricted to developing countries
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solving challenge of cost of vaccine development
reducing cost of vaccine is one measure of ensuring that a larger population can afford the vaccine and that the vaccine can be used by developing countries
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the cold chain and vaccine development
1. live-attenuated vaccine (most effective for long-term immunological memory) need to be stored and transported in specific conditions (refrigeration
2. if cold chain is broken, the vaccine risks losing potency or becoming unusable
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solving the challenge of the cold chain and vaccine development
a vaccine that doesn’t require refrigeration reduces cost associated with storage and distribution and ensures it can be used in developing countries where refrigeration often exists
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continuous monitoring of vaccine development
1. if disease-causing agents evolve by changing or losing their major antigenic determinants the vaccine could lose its efficacy
2. if the vaccine is based on a variable antigen, the genetic variation of the pathogen must be continuously monitored
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example of continuous monitoring of vaccine development
high mutation rate of influenza virus means its antigenic determinants can change every year, thus the influenza vaccine must change in response
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antigenic determinants
antigen molecule which can be recognized and bound by an antibody
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the gold standard of vaccine development
1. even if a vaccine is approved it doesn’t mean the work is done
2. new strategies are developed to create better vaccines by using recombinant vector or by improving vaccine adjuvant
3. when a new version of an existing vaccine is developed, it must be as good or better than the existing version = gold standard conundrum
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vaccine development challenges of the influenza virus
1. flu vaccine to combat the influenza virus
2. structural nature of the virus impacts production of a one-for-all flu vaccine
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structural components of the influenza virus
1. neuraminidase antigen (NA)
2. hemagglutinin antigen (HA)
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Neuraminidase Antigen (NA)
surface protein that removes sialic acid from cell surfaces and enables new viral copies to infect and spread to other cells
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how many NA subtypes is there?
11 NA subtypes, each with sequence variabilities in their receptor
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hemagglutinin antigen (HA)
1. surface protein that recognizes and bind sialic acid on cell surface of glycoproteins
2. HA-cell surface interactions lead to endocytosis of the virus and the Has are activated to fuse the endosome and viral membrane
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how many hemagglutinin antigen subtypes are there?
18 HA subtypes, each with sequence variabilities in their receptor binding sites
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how many potential strains of influenza virus is there ?
18x11 = 198 potential strains of influenza virus
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what does having 198 strains of influenza mean?
explains why we can be vaccinated against the flu virus one year, but still get sick the next
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herd immunity
form of indirect protection from an infectious disease that occurs when a large proportion of the population is immune to an infectious agent
134
what type of population is herd immunity for?
provides a measure of protection for individuals who are not immunized, as it slows or completely stops spread of disease
- the greater proportion of individuals within a community who are immunized, the smaller the probability those who aren’t immunized will come in contact with the infectious agent
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who is herd immunity important for?
immunocompromised individuals who cannot be vaccinated
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how is herd immunity measured?
by calculating the basic reproduction number, R nought (R0)
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R0 (R nought)
the average number of secondary cases in a totally susceptible population
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function of R0
1. determines the herd immunity threshold and therefore the immunisation coverage required to achieve elimination of an infectious disease
2. as R0 increases, higher immunisation coverage is requires to achieve herd immunity
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what is herd immunity important for?
fighting measles
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prevalence of cancer
1 in 2 Canadians will develop cancer in their lifetime
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cancer
an error in either cell growth or cell death, which can result in out-of-control growth of cells
(body has mechanisms in place to control the balance between these two things)
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cancer cells vs normal cells
1. do not need specific growth factors to divide, normal cells do
2. don’t respond to signals that cause normal cells to stop dividing
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cancer cells
self cells that have been altered to escape the normal growth-regulating mechanisms
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what causes the changes of normal cells into cancer cells?
result of alterations in DNA, which induces cell transformation
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cell transformation
the change that a normal cell undergoes as it becomes malignant (cancerous)
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what is cancer transformation a result of?
carcinogenic chemicals or radiation
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tumour
an abnormal mass of tissue
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what causes a tumour?
cancer cells continue to divide and grow, ultimately forming a tumour
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immunotherapies
either based on secreted or cellular components of the IS
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purpose of immunotherapies
primarily aimed at enhancing host anti-tumour immune responses
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two types of tumours
1. benign
2. malignant
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benign tumour
not cancerous; unable to grow indefinitely or invade surrounding tissues
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malignant tumour
cancerous and has ability to metastasize
- continue to grow and become progressively invasive
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metastasis
colonization by tumour cells of sites different from their primary site of origin
- small clustered of cancerous cells will break off from the tumour and invade the surrounding blood or lymphatic vessels, travelling to different areas of the body where they can proliferate
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the resilience of cancer cells
cancer cells show resilience when in environments that a normal cell might not survive
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resilience
a cells ability to cope with environmental disturbances, and possibly even adapt for future exposure
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stress
an umbrella term for the harsh environmental exposures on tumour cells
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HeLa cell line origination
1. Henrietta lacks, donor of cells known as the HeLa cell line
2. Henrietta was diagnosed with carcinoma
3. sampled her ovarian cells without consent, and these cells were the first line of human cell culture to ever survive outside of the human body – immortality
159
breakthroughs involving the HeLa cells
1. recombinant protein production
2. HPV vaccine
3. understanding virology
4. toxicity testing
5. monoclonal antibody (mAB) production
6. polio vaccine
7. genome sequencing
8. telomerase activity
160
recombinant protein production
although bacterial cells can be utilized for protein production, they lack the required mechanics to produce more complex proteins
- HeLa cells line allowed researchers to overcome this challenge
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HPV vaccine
researchers found that HeLa cells were infected with HPV-18 virus, which led to HPV vaccines
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understanding virology
experimental viral infection on HeLa cells allowed researchers to characterize how specific viruses can evade the IS, such as CD4 T-cell receptor utilization by HIV
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toxicity testing
HeLa cells are now used to test cytotoxicity of drugs because hepatocytes were too unstable for a sustained use
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monoclonal antibody (mAB) production
monoclonal antibodies, which can be produces using hybridoma crosses of HeLa and other animal cells, have many applications such as medical diagnoses and cancer therapy
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polio vaccine
HeLa cells were the only human cells that could be used to test the polio vaccine
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genome sequencing
HeLa cells fused with mouse cells because the first hybrid cells, the fusion of two cell types
- aided the emergence of the human genome project
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telomerase activity
Gregg morin isolated telomerase from HeLa cells, which were previously found in animal embryos
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what hypothesis did telomerase activity support?
supported hypothesis that both embryos and cancer cells utilize telomerase to rapidly divide, giving researchers insight on the importance of telomerase in human embryology
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the cancer-immunity cycle
series of events that must occur in order for an effective IR to be initiated against cancer cells
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what does the cancer-immunity cycle decribe?
how the IS balances the recognition of an defense against, non-self molecules and prevention of autoimmunity
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step 1 of the cancer-immunity cycle
release of cancer cell antigens (cancer cell death)
- antigens are released by mutated cancer cells, indicating that they are not healthy cells
- IS can recognize these antigens
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step 2 of the cancer-immunity cycle
cancer antigen presentation (dendritic cells/APCs)
- cells of IS capture the released antigens and travel to lymph nodes where they find T-cells
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step 3 of the cancer-immunity cycle
priming and activation (APCs and T-cells)
- T-cells are activated by antigens and IR against the cancer cells is initiated
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step 4 of the cancer-immunity cycle
trafficking of T-cells to tumours (CTLs)
- the activated T-cells move through the blood vessel to site of tumour
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step 5 of the cancer-immunity cycle
infiltrations of T-cells into tumours (CTLs, endothelial cells)
- once the T-cells reach the cancerous cells, they invade the tumour and attack it
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step 6 of the cancer-immunity cycle
recognition of cancer cells by T-cells (CTLs, cancer cells)
- T-cells recognize cancer cells because of the antigens they had previously released
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step 7 of the cancer-immunity cycle
killing of cancer cells (immune and cancer cells)
- T-cells initiate a pathway that results in cancer cell death
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theory of tumour immunosurveillance
states that tumour cells are identified and kept under control by the IS of healthy individuals
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tumour and cancer cell progression
1. cancer cells sometimes evade the recognition by the IS, or magnitude of the anti-tumour IR is not sufficient to kill all of the cancer cells
2. often the immune environment around the cancer cells can promote tumour progression
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immunoediting
dynamic process which describes the connection between the tumour cells and the IS in context of immunosurveillance and tumour progression
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3 phases the cancer immunoediting process is constituted by?
1. elimination
2. equilibrium
3. escape
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phase 1 of cancer immunoediting
elimination
- when a tumour cell arises in a tissue, the IS can quickly act to remove it
- a variety of immune cells, including NK cells, cytotoxic cells and helper T-cells can recognize the altered cell and work to eliminate it
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phase 2 of cancer immunoediting
equilibrium
- if the tumour cells are not eliminated, they can enter a state of equilibrium wher the cell proliferation is matched by cell killing by the IS
- equilibrium phase can last for a short time or many years
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phase 3 of cancer immunoediting
escape
- tumour cells are no longer recognized by the IS and so avoid elimination
- these cells are able to grow uncontrolled and eventually proliferate to form a tumour
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what do the 3 phases of cancer immunoediting allow?
allow cancer cells to overcome the IR, proliferate and form tumours
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two mechanisms tumour cells use to avoid detection by the immune system
1. reduced MHC expression
2. poor co-stimulatory molecules
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reduced MHC expression
1. tumour cells display low levels of MHC class I molecules on their cell surface
2. as cytotoxic T lymphocytes (CTLs) recognize antigens in context of MHC class I molecules, an absence of these molecules will inhibit recognition of tumour cells
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poor co-stimulatory molecules
1. T-cells requires both expression of MHC and co-stimulatory molecules to become activated
2. tumour cells lack these co-stimulatory molecules, which contribute to poor immunogenicity
3. T-cells will only be partially activated
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new cancer therapies
should seek to improve the recognition of abnormal/potentially cancerous cells or strengthen the IR to abnormal/potentially cancerous cells
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cancer immunotherapy
1. immune cells don’t see the cancer cells as foreign and leaves them alone
2. new drugs affect interaction between IS and cancer cells – allows IS to see what the cancer cell is
3. focusing more on flagging cancer cell for immune system to attack not giving a drug to attack
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cancer drugs
drugs don’t activate ones immune system to attack cancer cells
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4 reasons immunotherapy has the potential to be highly effective to treat cancer?
1. able to attack cancerous cells throughout all organs in the body
2. allows IS to specifically target and eliminate cells without damaging healthy cells, resulting in fewer side effects, than traditional cancer treatments (traditional and chemotherapy)
3. takes advantage of immunological memory, allowing for possibility of long-term protection
4. can be applied to almost all types of cancers
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how would using immunotherapy as a cancer treatment affect the cancer-immunity cycle?
immunotherapy can be used to enhance the body's immune system in steps 2 and 7 of the cancer-immunity cycle
- presentation and destruction of antigens on cancerous cells
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most effect lymphocyte population in killing cancer cells
T-cells
- B-cell lymphocytes are also important
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B-cell lymphocytes
tumour infiltrating lymphocytes (TILs)
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what parts of TILs are suggested as a prognostic biomarker in some cancers?
type, density and location of TILs have been suggested as a prognostic biomarker in some cancers
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TILs as prognostic biomarkers
these TILs leave the bloodstream and migrate to infiltrate the tumour under influence of various chemotactic gradients of specific types of chemokines
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what can TILs be a mix of?
T- and B-cells
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number of TILs
not always reflective of their activity and prognostic significance
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dynamic phenotypic markers expressed on TILs
some reflect their activation status and therefore must accompany any interpretations on their roles as biomarkers for diagnosis, such as in the case of breast cancer
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prognostic biomarker
biological characteristics that are objectively measured and evaluated to predict the course of a disease or a response to a therapeutic intervention among patients with the same characteristic
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biomarkers
a measurable substance in an organism, the presence of which is indicative of some phenomenon such as disease, infection or environmental exposure
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T-cell inflamed ("Hot") tumours
show higher immune activity compared to cold tumours
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solid tumours
immunologically classified as either T-cell inflamed (“hot”) or T-cell non-inflamed (“cold”) tumours
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characteristics of the hot tumours
1. high numbers of CD8+ TILs
2. high levels of interferon (IFN) genes
3. usually respond well to treatment (chemotherapy and immunotherapy)
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T-cell non-inflamed ("Cold") tumours
show lower immune activity compared to hot tumours
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characteristics of the cold tumours
1. low numbers of CD8+ TILs
2. low levels of interferon (IFN) genes
3. usually inferior response to treatment (chemotherapy and immunotherapy)
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treatment of hot and cold treatments
1. one could convert cold tumours to hot by stimulating the tumour interferon activity
2. knowledge has led to the exploitation of anti-tumour immunity towards development of newer treatments
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a new immunotherapy tool
the immunoscore
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an immunoscore
measures the density/numbers of T-cells in the center (CT) and at the periphery (IM) of the tumour by immunochemistry
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what is the purpose of an immunoscore?
helps stratify patients as having high risk or low risk cancers, and aid in developing treatment plans
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workflow for determining an immunoscore
1. separating tumour in central (CT) and peripheral (IM) regions
2. staining for T-cells and conducting digital pathology
3. assigning a score to tumour to relate it with an associated diagnosis or risk attribution
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approaches used to unleash anti-tumour immunity
1. target immune inhibitory pathways in tumour microenvironment
2. promote immune activation in tumour microenvironment
