CBIO 5: Cancer Immunobiology Flashcards
1
Q
Observe the learning outcomes of this session
A
2
Q
What is the fundamental of the professional antigen-presenting cells?
Give an example of them
A
- dendritic cells: act as a bridge between innate and adaptive immune system
- They patrol the body in search of antigens that they present to T cells by displaying them on a complex of molecules called the Major Histocompatibility Complex (MHC) or Human Leucocyte Antigen (HLA).
- They serve a fundamental function - in fact, T cells are not able to detect antigens on their own and require the T cell receptor (TCR) to recognise antigens displayed on MCH
3
Q
What is an antigen?
A
- An antigen is a substance able to produce an immune response
- Antigens are usually peptides.
4
Q
What are the three types of tumour cell antigens?
Briefly describe them
A
- tumour specific antigens (TSA):
- Tumour specific antigens are present only in cancer cells and normally they are the product of a genetic aberration.
- An aberrant gene can be still transcribed and translated and the protein produced will be new to the immune system.
- tumour-associated antigens (TAA):
- As you have already learned cancer cells can increase the expression of some proteins that make them thrive, for example, some growth factor receptors
- The immune system is tolerant to these proteins because they are also present in normal cells.
- However, some TAAs are expressed at a very low level in normal cells and when expressed in higher levels within cancer cells they can trigger an immune response.
- They can also be used to develop some immune therapies.
- oncofetal antigens (TAA):
- Some proteins are expressed during early embryonic development and are switched off in adult life.
- These proteins are expressed before the immune system fully develops and acquires self-tolerance.
- Cancer cells have the ability to activate the transcription and translation of embryonic genes that make them thrive.
- Once these are active, the immune system encounters them for the first time and therefore is able to mount a response.
5
Q
Review the main characteristics of tumour antigens
- examples of antigen type
- approved immunotherapies for target antigen
A
6
Q
Look at the table
There is another group of antigens described in the table (Cancer/testis antigen). Read the description and select which category you think it most closely resembles:
- TSA
- TAA
A
- TAA
- because they are expressed by various tumour types but nevertheless are also expressed in normal tissues (in reproductive tissues
- so they are not only specific in tumour cells
7
Q
Which antigens would you consider safe to target and why?
- TSAs
- TAAs
A
- TSAs
- since they are only expressed on tumour cells
- TAAs are useful targets too
- e.g. ErbB2 is successfully targeted in breast cancer
8
Q
Find which of these antigens are expressed in cancer but not in normal cells?
- MAGE-A3
- Claudin3
- HER2
- HPV E6 and E7
A
- HPV E6 and E7
9
Q
What is immune surveillance?
A
- this is the stage when effectors cells play a fundamental role in the immune response to tumours
- they are capable of mounting a response that can effectively kill cancer cells
10
Q
What are some cells involved in immune surveillance?
A
- antigen presenting cells (APCs)
- helper T cells (THs)
- cytotoxic T lymphocytes (CTLs)
- natural killer cells (NK cells)
- B cells
- inflammatory macrophages (M1)
11
Q
What are the two types of antigen-presenting cells?
A
- professional antigen presenting cells
- non-professional antigen presenting cells
12
Q
Describe professional antigen-presenting cells
Give examples of them
How do they detect tumour antigens?
A
- These cells are very efficient at internalising and processing external antigens by phagocytosis.
- The resulting peptides are loaded into the Major Histocompatibility Complex II (MHC II) and displayed on the cell membrane.
- Dendritic cells (DC), macrophages and B cells are all professional antigen-presenting cells.
- Antigen-presenting cells may detect tumour antigen shed by tumour cells or they can sample fragments of tumour cells in and around the tumour microenvironment.
13
Q
Describe non-professional antigen-presenting cells
Give examples of them
How do they detect tumour antigens?
A
- These are all the nucleated cells in our body including antigen-presenting cells and they present self-antigens (both normal and mutated), or antigens that end up in the cytoplasm, for example, from viruses.
- These antigens are processed through the proteasome and loaded into the Major Histocompatibility Complex I (MHC I) in the endoplasmic reticulum and then displayed at the cell surface.
- As explained earlier when a normal self-antigen is displayed on MCH class I, the immune system does not mount a response, but when this is a mutated self-antigen or viral antigen it does.
14
Q
Describe how antigen-presenting cells activate T-cells
A
- The first signal required for T cells to attack cancer cells is an interaction between the MHC I/II and the T cell receptor (TCR).
- The second signal is the interaction between co-stimulatory molecules present on the surface membrane of T cells and APCs.
- A well-known example is the interaction between CD28, which is present on T cells, and CD80 and CD86 which are expressed on APCs.
- APCs release specific subsets of cytokines that provide further information to T cells allowing them to mount the most appropriate response.
15
Q
Describe immune checkpoints when it comes to T-cell activation
Why?
A
- T cell activation requires several switches because improper activation of T cells can have serious consequences.
- As such, once the immune response is completed, T cells need to return to a resting state.
- Alongside an activation mechanism, there is a mechanism that acts as a break so that the immune response is controlled.
- Examples of immune checkpoint receptors are cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1).
- When these are engaged with their respective ligands, CD80/86 and PD-L1/2, they send an “off” signal that places T cells at rest.
16
Q
Describe the ligand binding and affinity in this diagram for T-cell activation
A
- CD28 and CTLA4 share the same ligands CD80/86.
- However, the affinity of CTLA4 for CD80/86 is far superior to that of CD28.
17
Q
What are some of the functions of helper T cells?
A
- activate B cells to produce antibodies
- Induce better killing ability in macrophages
- Dampen the immune response when tolerance is required
- Help in the activation of cytotoxic T cells.
18
Q
Why is it that only professional antigen-presenting cells can present to helper T-cells?
A
- Helper T cells express CD4 on their surface and they are called CD4+ cells.
- CD4 is a co-receptor of the TCR that allows the recognition of antigens presented via MHC class II, as illustrated in the figure below.
- Therefore only professional antigen-presenting cells can present to helper T cells.
19
Q
Describe cytotoxic T lymphocytes
What antigens do they recognise?
A
- Cytotoxic T lymphocytes (CTLs) are professional killers.
- When they identify cells expressing viral or tumour antigens they release granules filled with toxic substances to kill the target cells.
- Potentially any cell in our body can become cancerous or infected by viruses and therefore antigen presentation to CTLs has to occur from all these cells.
- For this reason, CTLs recognise antigen presented via MHC class I, which is expressed by all nucleated cells.
- CTLs express the TCR co-receptor, CD8 that allows the specific recognition of antigens presented via MHC class I as illustrated in the figure below.
20
Q
Study this diagram of CTLs in action when dealing with a tumour cell
A
21
Q
Describe natural killer cells
- response in cancer cells
- activation
- mechanisms
A
- Natural killer cells (NK cells) are part of innate immunity.
- They are at rest when they detect inhibitory ligands that are superior to the activating ligands on the surface of target cells.
- MHC class I for example is an inhibitory ligand.
- However, viral infection including that with onco-viruses can downregulate the expression of MCH class I.
- Similarly, cancer cells with high mutation rates may produce aberrant MHC class I.
- As consequence, NK cells receptors are mostly engaged with activating ligands.
- Another cause of activation is the expression of stress signals.
- These are common in cancer cells and are caused by stressors such as DNA damage.
- When the stress/activating ligands are detected, NK cells become active and kill the target cells.
- Their killing mechanisms include the production of cytokines and cytotoxic mediators which induce apoptosis in the target cell.
- Have a look at the picture below that summarises the conditions for NK cell activation.
23
Q
Describe macrophages
- functions
A
- Macrophages are cells of the innate immunity and professional antigen-presenting cells.
- They serve an important function to eliminate pathogens and cell debris by phagocytosis.
- However, in the immune response to cancer, they have another important function:
- the antibody-dependent cell-mediated cytotoxicity (ADCC).
- Macrophages express the Fc receptor which is able to bind the Fc portion of an antibody when this is bound to a tumour antigen.
- Macrophages then release lytic enzymes, reactive oxygen and nitrogen species, and anti-tumour cytokines such as tumour necrosis alpha (TNF-a), as shown in the figure below.
29
Q
Describe the equilibrium phase of tumour immune editing
A
- If cancer cells are not completely eradicated during the tumour elimination phase, another transitory phase kicks in, called the equilibrium phase, in which the immune system and the developing tumour are in a balanced state.
- According to the theory of immune editing, during this phase – which can last for several years - tumour cells can remain dormant or keep on acquiring genome modifications (such as DNA mutations).
- This can result in the alteration of tumour-specific antigens which may no longer be recognised by the immune system.
- There is also equilibrium between tumour-promoting cytokines (e.g., IL-10, IL-23) and anti-tumour cytokines (e.g. IL-12, IFN-γ).
30
Q
Describe the escape stage of tumour immune editing
- list some of the mechanisms promoting it
A
In this phase, the immune system is unable to restrict tumour growth and cancer cells grow and expand uncontrollably.
- Clinical malignancies can emerge during the escape phase. Below are some of the mechanisms promoting tumour immune escape.
- Mutations:
- In the immune surveillance section, you have learned how powerful T cells are in mounting a response.
- They are also very specific and will recognise unique tumour antigens.
- However, since cancer cells mutate continuously, the cells specialised against the initial tumour antigens are of little use and a new set of cells need to be produced against the new mutated antigens.
- The prolonged antigen stimulation will lead to immune exhaustion with loss of T cell effector function.
- Low MHC molecule expression:
- Viruses can repress the expression of MHC molecules.
- Therefore in cancer caused by oncoviruses, loss of MHC is not uncommon.
- Similarly, cancer with a high rate of mutation may have aberrant expression of MHC.
- Lack of MHC will halt the recruitment and activation of T cells.
- In this instance, NK cells should be more active but often activating factors on target cells have also reduced expression.
- Lack of co-stimulatory signals:
- Tumour cells lack co-stimulatory signals.
- Earlier in this eModule you have learned that complete activation of T cells requires both antigen presentation and co-stimulatory signal.
- Complete activation of cytotoxic T cells requires support from helper T cells and professional antigen-presenting cells in a process called antigen cross-presentation.
- However, in the vicinity of the tumour, such support may be missing and T cells could be not completely activated.
- see figure 1
- Immunosuppressive environment:
- Cancer cells can induce the production of anti-inflammatory cytokines such as IL-10.
- These dampen the immune response inducing helper T cells to acquire a regulatory phenotype expressing CTLA-4. CTLA-4 compete with CD28 for CD80/86.
- This further leads to T cell anergy rather than activation.
- Similarly, in this environment, inflammatory macrophages can acquire an M2 or anti-inflammatory phenotype and will become unable of ADCC.
- Moreover, cancer cells can exploit immune checkpoints by expressing PD-1L and directly inducing T cells anergy.
- See Figure 2 below.
- Resistance to apoptosis:
- One of the main mechanisms of tumour cell eradication consists of apoptosis caused by Cytotoxic T lymphocytes, NK cells and macrophages.
- As part of the tumour/immune system co-evolution, tumour cells activate signalling pathways that lead to resistance to apoptotic signals.
31
Q
Study this figure of the main concepts of tumour editing
A
36
Q
Describe this therapy: Bacillus Calmette-Guérin (BCG) Therapy
- Mechanism
- Advantages
- Limitations
- Availability
A
- Mechanism:
- Intravesical administration of Mycobacterium bovis induces innate immune response
- induction of cytokine production and immune cell infiltration in the bladder urothelium
- Advantages:
- Allows bladder preservation (better quality of life)
- Most effective treatment for early stage high risk bladder cancer
- Limitations:
- Can be poorly tolerated: both local and systemic side effects
- Risk of BCG-related disease (active infection)
- Availability:
- Gold-standard treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), used to prevent disease recurrence as well as progression
37
Q
Describe this therapy: Adoptive Cell Therapy - Tumour Infiltrating Lymphocytes (TIL)
- Mechanism
- Advantages
- Limitations
- Availability
A
- Mechanism:
- T cells isolated from tumour biopsy are activated and selected ex vivo.
- This allows transfer of specific T cell population that recognizes tumour antigens.
- Advantages:
- Ability to target solid tumours
- High specificity due to targeting of clonal neoantigens
- Adapted to specific tumour microenvironment
- No need for genetic engineering
- Durable responses described: 3-5 years
- Limitations:
- Time consuming and costly manufacturing
- MHC dependent
- Inactive against tumour changes due to immune editing
- Availability:
- Clinical trials for Lifileucel: LN-144 successful in metastatic melanoma, LN-145 in cervical cancer
38
Q
Describe this therapy: Adoptive Cell Therapy - Engineered T Cell Receptor
- Mechanism
- Advantages
- Limitations
- Availability
A
- Mechanism:
- T cells engineered to allow introduction of T-cell receptors of defined specificity
- Advantages:
- Suitable for patients without efficient T cell immune response
- Can recognize intracellular antigen fragments
- Wide range of targets
- High affinity binding
- Limitations:
- Requires engineering of patient’s T cells
- MHC dependent
- Difficulty selecting suitable targets
- Possible toxicity due to mispairing of TCR α and β chains
- Availability:
- Large number clinical trials for ao melanoma, multiple myeloma, several solid tumours.
- Many different targets described (ao p53, CEA, MAGE)
39
Q
Describe this therapy: Adoptive cell therapy - Chimeric antigen receptor (CAR-T cells)
- Mechanism
- Advantages
- Limitations
- Availability
A
- Mechanism:
- Combines the effector functions of T cells and the ability of antibodies to recognize pre-defined surface antigens with a high degree of specificity in a non-MHC restricted manner
- Advantages:
- MHC-independent antigen targeting
- Induction of T cell expansion upon interaction with antigen
- High affinity binding
- Enables production of high numbers of antigen-specific T cells
- Limitations:
- Low persistence in vivo
- Antigen cross-reactivity
- Can be impaired by immunosuppressive TME
- Requires engineering of patient’s T cells
- Requires optimal T cell-to-target cell spacing distance for T cell activation
- Can have severe side effects
- Availability: see first image
40
Q
Describe this therapy: NK Cell Therapy
- Mechanism
- Advantages
- Limitations
- Availability
A
- Mechanism: See image
- Advantages:
- Antigen non-specific, no need for antigen-specific priming
- Improved safety, lack of toxicity caused by cytokine release syndrome
- Multiple mechanisms to activate cytotoxicity
- Limitations:
- Difficulty to meet clinical-grade ex vivo expansion
- Limited in vivo persistence
- Limited infiltration in solid tumours
- Inactive against tumour changes due to immune editing
- Availability:
- Many clinical trials ongoing, for oa gastric, lung and liver cancer, HER2-specific CAR-NK cell for metastatic HER2+ breast cancer
41
Q
Describe this therapy: Preventative Cancer Vaccines
- Mechanism
- Advantages
- Limitations
- Availability
A
- Mechanism:
- Prevents infection with viruses that can cause oncogenic transformation
- Advantages:
• Specificity, low toxicity, preventative nature
- Limitations:
• Doesn’t prevent all cancers related to
specific virus (depending on the vaccine)
- Availability:
- HPV vaccine (Cervarix, Gardasil) approved for prevention of cervical, vaginal, vulvar and anal cancer
- Hepatitis B (oa Engerix B) vaccines approved for prevention of liver cancer
42
Q
Describe this therapy: Therapeutic cancer vaccines
- Mechanism
- Advantages
- Limitations
- Availability
A
- Mechanism: see image 1
- (Dis)Advantages:
• Specific immune response to tumour antigens, difficult target selection
- Availability:
• Sipuleucel-T (Provenge) for prostate cancer, antigen: prostatic acid phosphatase
43
Q
Describe this therapy: Immunomodulators - Checkpoint inhibitors
- Mechanism
- Advantages
- Limitations
- Availability
A
- Mechanism:
- Enhance anti-tumour immune response by blocking immune checkpoint molecules
- Cancer cells are no longer able to “turn off” T cells
- Advantages:
- Proven clinical benefits: durable responses, long term survival
- Proven efficiency in wide range of cancers
- Limitations:
- Variable efficacy
- Primary or acquired resistance
- Severe side effects
- Availability: see first image
46
Q
Describe this therapy: Bispecific Antibodies
- Mechanism
- Advantages
- Limitations
- Availability
A
- Mechanism:
- Simultaneous targeting of two tumour antigens
- Advantages:
- Selectivity
- Potential to modulate two functional pathways
- Increase binding specificity
- Relatively cheap
- Limitations:
- Larger molecules -> less intra-tumoral penetration
- Steric inhibition of engaging sites
- Potential to become inefficient due to hetero-dimerization of chains
- Availability:
- Two FDA approved: Catumaxomab (targets EpCAM and CD3) for malignant ascites and Blinatumomab (targets CD19 and CD3) for acute lymphoblastic leukemia
- >150 currently in clinical trials for
47
Q
Describe the anti-tumour activity of CTLs
A
- CTLs produce granzyme and perforins
- high level of tumour infiltrating lymphocytes (TILs) correlates with positive prognosis
48
Q
Describe the anti-tumour activity of NK cells
A
- NK cells recognise and kill target cells by an integrated balance of activating and inhibitory signals, which allow them to distinguish between healthy cells and target cells such as those virally infected or transformed:
- Lack of inhibitory signal (MHC I)
- Increase of activating signals
49
Q
Using this image, describe the anti-tumour activity of antibodies
A
- CDC: complement dependent cytotoxicity
- ADCC: antibody dependent cellular cytotoxicity
- ADCP antibody dependent cellular phagocytosis
