20 - Tumour Immunity Flashcards
What is lethality of malignant tumours due to
Uncontrolled growth within normal tissues, causing damage and functional impairment
What is the malignant phenotype of cancers reflected by
- 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
Immune surveillance
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
Demonstration of the existence of immune surveillance
Demonstrated by the increased incidence of some types of tumours in the immunocomprimised
Cells that produce the most effective response against naturally arising tumours
CD8 CTLs (little evidence for effective humoral immune response against tumours)
Defining characteristics of adaptive immunity that are exhibited in immune responses to tumours
- Specificity
- Memory
- Key role of lymphocytes
Tumour specific antigens
Antigens that are expressed on tumour cells but not normal cells (some are unique to tumours, others are shared)
Tumour associated antigens
Tumour antigens that are also expressed on normal cells (normal cellular constituents whose expression is dysregulated in tumours)
Products of mutated genes
- 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
Example of abnormally expressed but unmutated cellular proteins
- 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
MAGE
Melanoma associated antigens
Antigens of oncogenic viruses
- 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
Most immunogenic tumours known
Virus induced tumours because the viral peptides are foreign antigens
Oncogenic genes in HPV
E6 and E7
HPV vaccine
- 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
Oncofetal antigens
- 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)
Two best characterised oncofetal antigens
- Carcinoembryonic antigen (CEA)
- α-fetoprotein (AFP)
Tissue specific differentiation antigens
- 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
Lymphoma diagnosis
- 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
Tumour infiltrating lymphocytes (TILs)
Derived from the inflammatory infiltrate in human solid tumours, contain CTLs with the capacity to kill the tumour from which they are derived
Effective anti tumour antibodies
Work by ADCC
Effector CTL mediated killing of tumour cells
- 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
Application of APCs
- 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.
NK cells in tumour immunity
Kill many types of tumour cells, especially cells that have reduced class 1 MHC expression and express ligands for NK cell activating receptors
Escaping immune recognition by loss of antigen expression
- 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
Tumour immunoediting
Immune responses to tumour cells impart selective pressures that result in the survival and outgrowth of variant tumour cells with reduced immunogenicity
Mechanisms of immune evasion by tumours
- 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)
Phases of immune evasion
- 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
Tumour vaccines
- 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)
Immune checkpoint inhibitor therapies
- 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
Mechanisms of action of CTLA4
- 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
CD28 ligand
B7
Checkpoint protein inhibition
- CTLA4/B7 binding inhibits T cell activation
- Blocking CTLA4 allows T cell killing of tumour cell
- Same for PD-1
PD-1
Co-stimulatory molecule expressed on activated T cells that downregulates immune response
Blockage of PD1/PDL1 interaction with therapeutic antibodies
Blocking the PD-1/PDL1 interaction takes away the signal that prevented T cells from attaching to cancer cells and leads to tumour infiltration
Passive immunotherapy for tumours with T cells and antibodies
- 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
CARs
- 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
How do CARs engage target
Via single chain variable fragment (scFv) derived from antibody
Tumour specific monoclonal antibodies
May eradicate tumours by the same effector mechanisms that are used to eliminate microbes (opsonisation and
phagocytosis, complement activation, ADCC)
Problems with anti tumour antibodies
- 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