Anti-tumour Immunity and Immunotherapy for Cancer

Question 1

Describe cancer antigens as triggers of anti-tumour immunity

Answer 1

1) Tumour Specific Antigens (TSAs):

• Unique antigens present only on tumour cells
• Result of tumour-specific mutations and thus vary from one individual to another and individual tumours
• T cells recognise these antigens as non-self and trigger a targeted immune response to destroy the cells displaying these antigens

2) Tumour-Associated Antigens (TAAs):

• TAAs are present on normal cells as well as cancer cells but are usually over-expressed in tumour cells
• TAA include proteins or peptides that are ordinarily expressed during certain stages of development, like embryonic or fetal stages but are aberrantly expressed in tumour cells
• Also include cancer-germline or cancer-testis antigen, which are normally only expressed in germ cells but can be expressed in cancers
• The immune response to TAAs is usually weaker compared to TSAs due to T cell development where high affinity to self-antigens are deleted or not selected for growth to avoid autoimmunity

3) Oncofetal Antigens

• These antigens are proteins expressed only during fetal development and should be turned off after birth, but can be turned back on in tumour cells
• Alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) are examples of oncofetal antigens and are recognised by the immune system

4) Viral Antigens:

• HPV or Hepatitis B and C viruses can cause cancers
• Viral proteins are produced in the cancer cells, which can be recognised as foreign by the immune system and trigger an anti-tumour response

Question 2

Describe and explain how tumours escape the control initially exerted by the immune system

Answer 2

1) Loss or Alteration of Tumour Antigens:

• Tumour antigens, allow the immune system to recognise them as cancer cells and are abnormally expressed or mutated in cancer cells
• However, cancer cells can alter these antigens or stop expressing them, avoiding detection by immune cells
• This ability is also facilitated by the genetic instability of tumour cells, which allows for high variability and adaptability in antigen expression

2) Downregulation of MHC molecules:

• Cancer cells can reduce their expression of MHC class 1 molecules thus reducing antigen presentation and reduced recognition by CTLs

3) Immune Checkpoint Proteins:

• Exploit immune checkpoint pathways to avoid immune destruction
• Many tumours over express PD-L1, a ligand for the PD-1 receptor on T cells
• When PD-L1 binds to PD-1, it sends an inhibitory signal that reduces T-cell activity, suppressing immune response

4) Secretion of Immunosuppressive Factors:

• Producing cytokines like TGF-β and IL-10 which suppress the activity of effector T cells and promote the induction of regulatory T cells
• Tumours can also secrete factors like VEGF, which inhibit the maturation of dendritic cells

5) Recruitment of Immunosuppressive cells:

• Recruit regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) to their microenvironment, which suppress the activity of effector immune cells

6) Induction of T-cell Exhaustion:

• Chronic exposure to antigens can lead to a state of T-cell exhaustion, where T cells lose their effector function and become unresponsive
• By persistently presenting antigens to T cells, leading to their functional impairment

7) Alteration of Metabolic Landscape:

• Induce hypoxia, which inhibits the activity of immune cells
• Also consume essential nutrients from the microenvironment, depriving immune cells of the resources needed for their function

8) Epithelial-to-Mesenchymal Transition (EMT):

• Tumours can undergo EMT, a process in which they gain migratory and invasive properties
• Increase resistance to immune cells and is associated with an immunosuppressive tumour microenvironment

Question 3

Identify the main effector functions of both antibodies and cellular responses against tumours

Answer 3

Antibody-mediated Anti-tumour:

1) Direct Anti-tumour Effects:

• Antibodies bind to tumour antigens, leading to direct inhibition of signalling pathways vital for tumour growth and survival

2) Antibody-dependent Cellular Cytotoxicity (ADCC):

• Antibodies bound to tumour cells (targeting TAAs and TSAs) are recognised by NK cells through their Fc receptors
• Triggers release of cytotoxic granules from the NK cell, inducing apoptosis

3) Complement-dependent Cytotoxicity (CDC):

• antibodies binding to tumour activates the complement system causing the formation of MAC which causes direct cell lysis

4) Opsonisation:

• Antibodies opsonise tumour cells, enhancing their recognition and phagocytosis by APC

Cellular Immune Responses Against Tumours:

1) CTLs:

• Recognise and respond to tumour antigens presented by MHC 1 molecules on the surface of tumour cells
• Upon recognition, release perforin and granzymes causing apoptosis

2) Th cells:

• CD4+ T cells aid CTLs and B cells in anti-tumour response
• By producing cytokines, such as IL-2 which promotes CTL proliferation and survival and also stimulates B cells to produce antibodies
• Enhancing the cytotoxic activity of macrophages and promoting differentiation of CTLs

3) NK cells:

• Recognise and kill tumour cells that have downregulated their MHC class 1 molecules by releasing perforin and granzymes

4) Macrophages:

• Tumour-associated macrophages (TAMs) either promote or inhibit tumour progression depending on the signals they receive
• M1 macrophages have antitumor effects, whereas M2 macrophages can promote tumour growth
• Phagocytosis of tumour cells and the release of pro-inflammatory cytokines are key anti-tumour activities of macrophages

Question 4

Describe and explain the therapeutic aims and mechanisms of action of a group of immunotherapies currently used in the clinic to treat cancer

Answer 4

1) Monoclonal Antibodies (mAbs):

• Monoclonal antibodies are made to target specific antigens on cancer cells, allowing a more precise attack
• When mAbs attach to a cancer cell, they can block growth signals and flag them for destruction by the immune system (opsonisation); or they can deliver radiation/toxin directly to the cancer cell
• For example, the mAb trastuzumab targets HER2, a protein over-expressed in some breast and stomach cancers, and works by blocking the protein’s signalling pathway that stimulates cell division

2) Immune Checkpoint Inhibitors:

• Checkpoint proteins on immune cells act like switches that need to be turned on (or off) to start an immune response
• Cancer cells can sometimes ‘trick’ these switches and avoid being attacked by the immune system
• Immune checkpoint inhibitors work by preventing this deception, allowing the immune cells to attack cancer cells
• pembrolizumab and nivolumab target the PD-1 checkpoint, freeing up T cells to attack cancer cells, while ipilimumab targets CTLA-4, another checkpoint that regulates T-cell function

3) Cancer Vaccines:

• Stimulate the immune system to attack specific targets
• Sipuleucel-T, a therapeutic vaccine for prostate cancer, is made by isolating immune cells from the patient, exposing them to a prostate cancer antigen in the lab, and then re-infusing them into the patient to stimulate an immune response

4) Adoptive Cell Transfer (ACT):

• Includes CAR-T cell therapy, where T cells from a patient are modified in the lab to express receptors on their receptor that can recognise and bind to proteins on cancer cells
• These modified T cells are then infused back into the patient
• Kymriah and Yescarta are CAR-T cell therapies approved for certain types of lymphomas and leukaemias

5) Oncolytic Virus Therapy:

• Oncolytic viruses are viruses that preferentially infect and kill cancer cells
• Also stimulate an immune response against the cancer cell
• T-VEC is a modified herpes virus that’s used to treat advanced melanoma
• The virus is injected directly into the melanoma lesions, where it replicates inside cancer cells causing them to rupture and die

6) Bispecific T Cell Engagers (BiTEs):

• Simultaneously bind to CD3 on T cells and a specific antigen on cancer cells which brings the T cells close to the cancer cells and triggers a T-cell response
• blinatumomab is a BiTE that binds to CD19 on B cells and CD3 on T cells, leading to T-cell-mediated killing of B-cell leukemias and lymphomas