20 - Tumour Immunity

Question 1

What is lethality of malignant tumours due to

Answer 1

Uncontrolled growth within normal tissues, causing damage and functional impairment

Question 2

What is the malignant phenotype of cancers reflected by

Answer 2

• Defects in regulation of cell proliferation
• Resistance of the tumour cells to apoptotic death
• Ability of the tumour cells to invade host tissues and metastasize to distant
  sites
• Tumour evasion of host immune defense mechanisms

Question 3

Immune surveillance

Answer 3

Physiologic function of the immune system is to recognise and destroy clones of transformed cells before they grow into tumours and to kill tumours after they are formed

Question 4

Demonstration of the existence of immune surveillance

Answer 4

Demonstrated by the increased incidence of some types of tumours in the immunocomprimised

Question 5

Cells that produce the most effective response against naturally arising tumours

Answer 5

CD8 CTLs (little evidence for effective humoral immune response against tumours)

Question 6

Defining characteristics of adaptive immunity that are exhibited in immune responses to tumours

Answer 6

• Specificity
• Memory
• Key role of lymphocytes

Question 7

Tumour specific antigens

Answer 7

Antigens that are expressed on tumour cells but not normal cells (some are unique to tumours, others are shared)

Question 8

Tumour associated antigens

Answer 8

Tumour antigens that are also expressed on normal cells (normal cellular constituents whose expression is dysregulated in tumours)

Question 9

Products of mutated genes

Answer 9

• Oncogenes and mutated tumour suppressor genes produce proteins that differ from normal cellular proteins and, therefore, can induce immune responses
• Presented on MHC class 1 molecules

Question 10

Example of abnormally expressed but unmutated cellular proteins

Answer 10

• Tyrosinase (enzyme involved in melanin biosynthesis that is expressed
  in normal melanocytes and melanomas)
• Tyrosinase is normally produced in such small amounts and in so few cells that it is not recognized by the immune system and fails to induce tolerance
• The increased amount produced by melanoma cells is able to elicit immune responses

Question 11

MAGE

Answer 11

Melanoma associated antigens

Question 12

Antigens of oncogenic viruses

Answer 12

• The products of oncogenic viruses function as tumour antigens and elicit specific T cell responses that may serve to eradicate the tumour
• Virus encoded tumour antigens are not unique for each tumour but are shared by all tumours induced by
  the same type of virus

Question 13

Most immunogenic tumours known

Answer 13

Virus induced tumours because the viral peptides are foreign antigens

Question 14

Oncogenic genes in HPV

Answer 14

E6 and E7

Question 15

HPV vaccine

Answer 15

• Composed of recombinant HPV capsid proteins from the most common oncogenic strains of HPV which form virus like particles
• No genomic material and therefore no activator of innate immunity

Question 16

Oncofetal antigens

Answer 16

• Proteins that are expressed at high levels in cancer cells and in normal developing foetal but not adult tissues
• Genes encoding these proteins are silenced during development and are de-repressed with malignant transformation
• Provide markers that aid in tumour diagnosis (and inflammation)

Question 17

Two best characterised oncofetal antigens

Answer 17

• Carcinoembryonic antigen (CEA)
• α-fetoprotein (AFP)

Question 18

Tissue specific differentiation antigens

Answer 18

• Tumours may express molecules that are normally expressed only on the cells of origin of the tumours and not on cells from other tissues
• Specific for particular lineages or differentiation stages of various cell types

Question 19

Lymphoma diagnosis

Answer 19

• Diagnosed as B cell derived tumours by the detection of surface markers characteristic of this lineage (e.g. CD20)
• Antibodies against these molecules are also used for tumour immunotherapy

Question 20

Tumour infiltrating lymphocytes (TILs)

Answer 20

Derived from the inflammatory infiltrate in human solid tumours, contain CTLs with the capacity to kill the tumour from which they are derived

Question 21

Effective anti tumour antibodies

Answer 21

Work by ADCC

Question 22

Effector CTL mediated killing of tumour cells

Answer 22

• Most tumour cells are not derived from APCs and therefore do not express the co-stimulators needed to initiate T cell responses, or the class II MHC molecules needed to stimulate helper T cells that promote the differentiation of CD8+ T cells.
• Once effector CTLs are generated, they are able to recognize and kill the tumour cells without a requirement
  for costimulation

Question 23

Application of APCs

Answer 23

• Grow dendritic cells from a patient with cancer
• Incubate the APCs with the cells or antigens from that patient’s tumour
• Use these antigen-pulsed APCs as vaccines to stimulate anti-tumour T cell responses.

Question 24

NK cells in tumour immunity

Answer 24

Kill many types of tumour cells, especially cells that have reduced class 1 MHC expression and express ligands for NK cell activating receptors

Question 25

Escaping immune recognition by loss of antigen expression

Answer 25

• Through tumour immunoediting
• E.g. When tumours are induced in either immunodeficient or immunocompetent mice and the tumours are then transplanted into new immunocompetent mice, the tumours that were derived from the immunodeficient mice are more frequently rejected by the recipient animal’s immune system than are the tumours derived from the immunocompetent mice

Question 26

Tumour immunoediting

Answer 26

Immune responses to tumour cells impart selective pressures that result in the survival and outgrowth of variant tumour cells with reduced immunogenicity

Question 27

Mechanisms of immune evasion by tumours

Answer 27

• Failure to produce tumour antigen leading to lack of recognition by CTLs
• Downregulation of class 1 MHC expression leading to lack of recognition by CTLs
• Secretion of immunosuppressive proteins or expression of inhibitory cell surface proteins (e.g. TGF-beta, Tregs)

Question 28

Phases of immune evasion

Answer 28

• Elimination phase: When tumour cells arise, a number of immune cells can recognise and eliminate them
• Equilibrium phase: Variant tumour cells arise and are more resistant to killing, over time a variety of different variants develop
• Escape phase: One variant escapes killing mechanism or recruits Tregs to protect it, allowing spread

Question 29

Tumour vaccines

Answer 29

• Immunisation of tumour bearing individuals with tumour antigens may result in enhanced immune responses against tumour
• Most are therapeutic vaccines (given after host has tumour, not before)

Question 30

Immune checkpoint inhibitor therapies

Answer 30

• Novel group of monoclonal antibodies with proven effectiveness in a wide range of malignancies
• Promote an anti tumour immune response by blocking signalling via either the CTL antigen 4 (CTLA4) or programmed cell death protein (PD-1) pathway

Question 31

Mechanisms of action of CTLA4

Answer 31

• Blocking CTLA-4 with antibodies results in increased immune responses to tumours
• CTLA-4 expression is low on most T cells until the cells are activated by antigen, and once expressed CTLA-4 terminates continuing activation of these responding T cells
• Expressed on regulatory T cells and mediates the suppressive function of these cells by inhibiting the activation of naive T cells

Question 32

CD28 ligand

Answer 32

B7

Question 33

Checkpoint protein inhibition

Answer 33

• CTLA4/B7 binding inhibits T cell activation
• Blocking CTLA4 allows T cell killing of tumour cell
• Same for PD-1

Question 34

PD-1

Answer 34

Co-stimulatory molecule expressed on activated T cells that downregulates immune response

Question 35

Blockage of PD1/PDL1 interaction with therapeutic antibodies

Answer 35

Blocking the PD-1/PDL1 interaction takes away the signal that prevented T cells from attaching to cancer cells and leads to tumour infiltration

Question 36

Passive immunotherapy for tumours with T cells and antibodies

Answer 36

• Treatment using T cells expressing chimeric antigen receptors (CARs)
• Isolate lymphocytes from blood and expand in culture using IL-2 (and add CAR gene)
• Transfer back into patient leads to tumour regression by both direct cytotoxic and cytokine mediated mechanisms

Question 37

CARs

Answer 37

• Synthetic, engineered receptors that can target surface molecules in their native conformation
• Unlike TCRs, engage molecular structures independent of antigen processing by target cell and independent of MHC

Question 38

How do CARs engage target

Answer 38

Via single chain variable fragment (scFv) derived from antibody

Question 39

Tumour specific monoclonal antibodies

Answer 39

May eradicate tumours by the same effector mechanisms that are used to eliminate microbes (opsonisation and
phagocytosis, complement activation, ADCC)

Question 40

Problems with anti tumour antibodies

Answer 40

• The selection (evolution) of variants of the tumour cells that no longer express the antigens that the antibodies recognise
• Avoided by use of cocktails of antibodies specific for different antigens expressed on the same tumour