The Immune System vs. Cancer

Question 1

What are the 6 hallmarks of cancer?

Answer 1

• Activating invasion and metastasis
• Enabling replicative immortality
• Inducing angiogenesis
• Resisting cell death
• Sustaining proliferative signaling
• Evading growth suppressors

Question 2

Describe how the immune system initiates angiogenesis.

Answer 2

• Cells of the innate immune system initiate angiogenesis and can protect against drugs targeting endothelial cell signalling (e.g. anti-VEGF therapy):
  
  • Macrophages
  • Neutrophils
  • Mast cells
  • Myeloid progenitors

Question 3

What are the emerging hallmarks and enabling characteristics of cancer?

Answer 3

Question 4

The density of immune cells can be used to predict prognosis in cancer.

The presence of which immune cells indicate good prognosis?

And which indicate poor prognosis?

Answer 4

• Good prognosis
  
  • High CD8
  • High CD4
  • High M1 macrophage
• Poor prognosis
  
  • High density of M2 macrophages

Question 5

What are the prognostic scores used to predict prognosis of cancer based on immune cells?

Answer 5

• Immunoscore is a trademarked prognostic score that measures the density of CD3 and CD8 cells in dstinct regions of the tumour.
• Tumour Bud Immuno Spatial Index (TBISI) measures CD3 and CD8 lymphocytes, cancer cells and their spatial relationship.

Question 6

What is immunosurveillance?

Answer 6

• A physiologic function of the immune system to recognise and destroy clones of transformed cells before they grow into tumours and to kill tumours after they are formed.
• Solid tumours have managed to avoid detection by the immune system or have been able to limit the extent of immunological killing, thereby evading eradication.
• The immune system therefore operates as a significant barrier to tumour formation and progression.

Question 7

What is immunoediting?

Answer 7

• Highly immunogenic cancer cell clones are routinely eliminated in immunocompetent hosts, leaving behind only weak immunogenic variants to grow and generate solid tumours.
• The tumour immuno-editing concept is divided into 3 phases:
  
  • Designated elimination
  • Equilibrium
  • Escape

Question 8

Describe the designated elimination phase of immunoediting.

Answer 8

Transformed cells escaping intrinsic control are subjected to extrinsic tumour suppressor mechanisms that detect and eliminate developing tumours before they become clinically apparent.

Question 9

Describe the equilibrium phase of immunoediting.

Answer 9

A phase of tumour dormancy where the tumour cells and immunity enter a dynamic equilibrium that keeps tumour expansion in check but does not kill it completely.

Question 10

Describe the escape phase of immunoediting.

Answer 10

Tumour cells emerge that either display reduced immunogenicity or engage a large number of possible of tumour suppressive mechanisms to inhibit anti-tumour responses leading to the progressive growth of those tumours.

Question 11

For a tumour to be present and clinically detectable, the immune responses must have failed to prevent the growth of the tumours. What are the possible reasons for this?

Answer 11

• Many tumours have developed specialised mechanisms for subverting and inhibiting immune responses.
• Tumour cells lose the expression of antigens which may be recognised by host immune system.
  
  • So even tumours which elicit effective immune responses may become less immunogenic over time because some clones that do not express immunogenic antigens have a selective survival advantage.
• Rapid growth and spread of tumour may overwhelm the capacity of the immune system to effectively control the tumour which requires that all malignant cells be eliminated.

Question 12

What does the existence of specific antitumour immunity imply?

Answer 12

The existence of specific antitumor immunity implies that tumors must express antigens that are recognized as foreign by the host.

Question 13

Describe how a neoantigen is formed.

Answer 13

• Normal cells express MHC class 1 (self) so there is no responding T cell because this is recognised as ‘self’.
• Mutations to normal proteins can change this self protein / antigen that the patient is tolerant of, and becomes recognised by T cells and elicits a T cell response.

Question 14

Describe how an oncogenic virus can cause a T cell response.

Answer 14

• Some viruses which infect cells and cause cancer (oncogenic) display their viral peptides on the cancer cells which stimulates a T cell response to the tumour.

Question 15

Describe how non-mutated tumour antigens cause a T cell response.

Answer 15

• Overexpression of proteins, even if they are unmutated by cancer cells can also cause an immune response. These tumour antigens include genes that would not be expressed by most adult cells.
• A – most of the genes expressed in development are repressed by methylation, but these can become demethylated and cancerous. These are abnormally expressed proteins which the immune system would not expect to see expressed on these cells.
• B – other genes may be amplified in cancer cells and cause overexpression. For example, overexpression of HER2 in breast CA which is detected by the immune system.
• C – there are also tissue specific antigens which can be expressed by both normal and cancer cells from the same tissue type. But, due to gene dysregulation or the abundance of the cancer cells expressing the gene, there is too much of this protein. The immune system understands this and elicits an immune response.

Question 16

What is lymphocyte differentiation?

Answer 16

• Lymphocyte differentiation is a process in which activated B cells or T cells become specialised immune cells.

Question 17

Explain the sequence of events when naïve B and T cells are exposed to an antigen-presenting cell.

Answer 17

• Naïve T cells are exposed to antigen by antigen-presenting cells, such as dendritic cells.
• Activation of T cells by antigen results in their clonal expansion or high proliferation of the specific T cell that recognises that specific antigen.
• The activated lymphocytes then differentiate into cells that are capable of killing the cells expressing that antigen.
• These are effector T cells, for example cytotoxic T cells.
• They can also differentiate into memory T cells which mount a quick and strong response to repeat exposure to that same antigen.
• After elimination of the infection, the effector T cells can become exhausted and undergo apoptosis, while memory cells remain.
• The naïve B cells recognise antigen and differentiate into plasma cells that secrete different classes of antibodies. This adaptive immune system takes ~21 days.

Question 18

Describe CD8⁺ T cell response to tumours.

Answer 18

• Cytotoxic (CD8⁺) T cells are the most important contributors to host immune defence against tumours.
  
  • They are the most prominent anti-tumour cells.
• Main mechanism against tumours by the immune system is killing cancer cells by CD8⁺ cytotoxic T lymphocytes (CTLs).
• They perform a surveillance function by recognising and killing cancer cells expressing tumour antigens.
• Tumour cells or their antigens are ingested by host antigen-presenting cells, such as dendritic cells.
• Peptides from antigens presented on MHC class 1 molecules for recognition by CD8⁺ CTLs.

Question 19

Describe CD4⁺ T cell response to tumours.

Answer 19

• CD4⁺ helper T cells (Th-1 cells) contribute to antitumor immune responses.
  
  • Dendritic cells carry the tumour antigens to the lymph nodes and co-localise with the naïve T cells. The antigen presenting cells express co-stimulators and these, for T helper cells which are activated at the same time, provide the signals needed for differentiation of the naïve CD8 cells into tumour specific killing cytotoxic T cells.
  • Once effector cytotoxic T lymphocytes are generated, they are able to recognise and kill the tumour cells in any tissue without requirement for co-stimulation.
• Anti-tumour effect due to their role in priming and activating the CTL response.
• They also activate macrophages.
• Through expression of cytokines, such as Interleukin-2 and interferon gamma 1 (IFN-γ) (among others), which increases tumour cells sensitivity to lysis by CTLs.

Question 20

Describe the role of macrophages in the immune response against cancer.

Answer 20

• Macrophages are capable of both inhibiting and promoting the growth and spread of cancers, depending on their activation state.
• M1 phenotype macrophages are anti-tumourogenic.
• Still unsure exactly how M1 macrophages are activated by tumours.
• Can be driven by the expression of IFN-γ secreted by Th-1 helper T cells.
• M1 macrophages kill tumours by:
  
  • Direct killing - producing nitric oxide or tumor necrosis factor as well as by phagocytosis.
  • Indirect killing - recruiting other immune cells like CTLs.

Question 21

Describe how the immune system can promote tumour growth.

Answer 21

• Chronic inflammation can promote the development of cancer.
• During cancer cell escape, immune editing selects for aggressive clones that are less immunogenic.
• Cells of innate immune system tend to be more tumour promoting.
• Innate immune cells can contribute to the mutagenesis of cancer cells through production of free radicals causing DNA damage.
• Release of NF-κB by cells of innate immune system promotes cancer progression.
• Adaptive immune cells:
  
  • CD4⁺ regulatory T cells (Tregs) – tumour can recruit Tregs, which in turn supress the activation of Th-1, CTLS and macrophages.

Question 22

Describe the role of M2 macrophages in cancer progression.

Answer 22

• The M₂ macrophage phenotype promotes tumour growth and spread:
  
  • M2 cells promote angiogenesis through vascular endothelial growth factor (VEGF).
  • M2 cells promote invasion through production of matrix metalloproteinases (MMPs).

Question 23

Describe the B cell response to tumours.

Answer 23

• Role of B cells in cancer progression is less well-understood.
• Evidence suggests that a high presence of B cells promotes tumour progresson.
• Lack of mature B cells decreases tumour progression.
• B cells can promote both angiogenesis and tumour cell proliferation.
• They do so by secreting molecules such as Interleukin-10 and TGF-β.

Question 24

Describe the role of immune checkpoints in cancer.

Answer 24

• Immune checkpoints are signalling pathways that inhibit the immune response (keep it in check).
• They stop autoimmunity and tissue damage by inactivating CTLs.
• These are important as uncontrolled immune responses can cause tissue damage.
• The 2 most understood T cell inhibitory pathways are:
  
  • CTLA-4 (cytotoxic T-lymphocyte-associated protein 4).
  • PD-1 (programmes cell death protein 1).
• The expression of both receptors on T cells inhibits their cytotoxic function, specifically when bound to their inhibitory ligands.
• Their expression alongside other proteins can cause an ‘exhausted’ T cell phenotype.

Question 25

How do tumours evade the immune system?

Answer 25

• Tumour cells express and secrete PDL-1.
• Tumour infiltrating lymphocytes express upregulated CTLA-4 and PD-1.
• Loss of tumour antigens.
• Mutations in the MHC genes.

Question 26

What is the role of immunotherapy in cancer?

Answer 26

• Classic chemotherapy often targets proliferating cells.
  
  • Can have a negative effect on the anti-tumour immune system.
• Immunotherapy can help promote the immune system’s fight against cancer.
• Immune responses to tumours can be specific to the tumour cells.
  
  • This could limit the toxic side effects of chemotherapy.

Question 27

How do checkpoint blockades work?

Answer 27

• Antibody therapies that bind to checkpoint receptors and blockade their T cell inhibiroty action.
• Blocking of CTLA-4, PD-1 or PDL-1 using antibody therapy can be highly effective in treating cancer, as they block the inhibition of the T cells.
• CTLA-4 was the first MAB drug approved - Ipilimumab. For treating advanced melanoma patients.
• Anti-PDL-1 / PD-1 therapy seem more effective at promoting CTLs to kill tumour cells. Also seem to have less side effects.
  
  • Have been approved in many cancers, including:
    
    • Colon
    • Bladder
    • Melanoma
    • Lung
    • Renal
  • Side effects:
    
    • Autoimmune and inflammatory reactions
• HOWEVER, >50% of patients treated with checkpoint blockades do not respond.
  
  • Because some have few new antigens and low mutation burden.