Lecture 21 - Cancer immunology Flashcards
What are the functions of the tumour microenvironment (TME)?
Two major functions:
* Pro-tumour: promotes tumour cell metastasis, growth and development in distal tissues
o Resisting cell death
o Sustaining proliferative signalling
o Evading growth suppressors
o Activating invasion and metastasis
o Enabling replicative immortality
o Inducing angiogenesis
o Deregulating cellular energetics
o Genome instability and mutation
o Avoiding immune destruction
o Tumour-promoting inflammation
* Immunosuppression
o Cancer is a disease to self immune system is taught to be self-tolerant
What are the clinical observations that point towards anti-tumour immunity?
- Lymphoid infiltration of cancers e.g., hot vs cold tumour
o Type, location, density
o Immunoscore > prognosis - Immunodeficiency/immunosuppression
o Primary (inherited) immunodeficiencies & immunodeficient mice more susceptible to cancer
o Infection
o Transplantation
o Immunosuppression increases risk of viral induced cancers
o In all forms of immunodeficiency, the relative risk of developing tumours in which oncogenic viruses are known to play a role is greatly increased
How do mouse models provide direct evidence for tumour immunity?
Left: mice injected subcutaneously with MCA to cause tumour cells to develop – conclusion: original mice have pre-existing resistance to the tumour antigens unlike the naïve mice who developed tumours. When you take CD8+ T cells and place them in the naïve cells, the tumours are prohibited from developing which suggests that the resistance to tumour antigens occurs where cytotoxic T cells develop
Right: tumour cells in immunised mice are irradiated, subsequently injected with viable tumour cells results in the rejection of these tumour cells – primed to these tumour cells. BUT if injected with viable cells of a different then there is a response to the irradiated tumour does not eliminate unrelated tumours of a different cell type. THEREFORE, tumour antigens different with each tumour
These experiments show the immune system can recognise and respond to tumour cells (antigens)
What are the types of tumour antigens?
Type of tumour antigen Antigen characteristics
Oncogenic viral proteins: Foreign antigens (non-self) only expressed in virus-infected cells
Mutated gene products: Mutated self-proteins expressed in tumour cells but not normal cells
Altered glycolipid/glycoproteins: Abnormal (mutated) tumour cell expression of surface glycoproteins and glycolipids
Aberrantly expressed: Unmutated proteins silenced in normal cells but derepressed or produced in excessive amounts in tumour cells
Cell-type specific differentiation: Unmutated self protein specific for cell lineages/differentiation stages
How do T cells view antigens?
- T cell receptor (TCR) rearranged during T cell development
- Every mature T cell clone expresses single rearranged TCR that binds to peptide-MHC complexes
- Generates highly diverse TCR repertoire
- MHC class I (endogenous peptides)
- MHC class II (exogenous peptides)
- All proteins, even self-peptides are fragmented and presented on MHC molecules
What is immunological tolerance?
Education process whereby lymphocytes are taught not to respond to the host self-antigen
* State of antigen unresponsiveness induced by exposure of lymphocytes to that antigen
What is the role of CD8+ cytotoxic T lymphocytes (CTL)?
- Directly lyse cancer cells presenting tumour-derived peptides (antigen) on MHC-I (perforin, granzymes)
- Considered major player in anti-tumour responses (clonal and directly kills tumour cells)
- CD8+ ‘tissue resident memory’ T cells (TRM) strongly implicated in local anti-tumour immunity
- Requires help from intratumoral CD4+ T cells
What is the role of CD4+ T helper cells?
- Recognise shed (exogenous) tumour-specific Ag/MHC-II on antigen presenting cell (APC)
- Produces cytokines direct tumoricidal/tumour cytostatic roles e.g., IFN-gamma and TNF (Th1)
- Provides help for differentiation of tumour specific CD8+ CT
What is the adaptive immunity response to tumours?
- Dendritic cell can present exogenously derived antigen via MHC-I pathway and primes CD8 T cells
- Cross-presentation
- Involvement of signal 1: MHC on dendritic cell presenting the peptide and signal 2: activated CD4+ T cell providing help to become armed effector CTL
- Anergy occurs when there is no signal 2
B cells/antibody
* B cells develop antibodies to tumour antigens
o Antibodies to tumour antigen detect detected in cancer patients
o Circumstantial evidence that antibodies = prognosis
* Complement-mediated tumour cell lysis
* Fc region of antibody engages Fc receptor (FcR+) cells
o Antibody-dependent cellular phagocytosis (ADCP): macrophage
o Antibody-dependent cellular cytotoxicity (ADCC): NK cells (CD16)
* CD16 genotype effects ADCC and clinical efficacy of therapeutic mAbs
o Cd16 158VV have a higher affinity for IgG than CD16 158FF
What are the key features of CD4+ T cell help?
- CD4+ T cell help is essential for the priming of CTL by cross-presented tumour antigens
- Dendritic cells help relay CD4+ T cell-derived help signals to CTL
- Large part of the help signal originates from CD40L-CD40 interaction
- Tumour-specific CD4+ T helper cells are required at the tumour site
- Required for maintenance of tumour-specific memory CTL
How do dendritic cells cross-present tumour antigens to CTL?
- Cross presentation = unique ability of dendritic cells that express the Batf3 transcription factor to present exogenously derived tumour antigens on MHC-1
- Activated CD8+ T cells upregulated cytokines to kill the tumour cell
What are regulatory T cells?
- Express a T cell receptor biased towards self-peptides
- Function to suppress immune responses and maintain self-tolerance
- Secretes immunosuppressive cytokines e.g., TGF-B, IL-10
- Higher in cancer patients, recruited to tumours – associated with suppression of anti-tumour immunity and poor prognosis
How is a personalised peptide vaccine possible?
- Express a T cell receptor biased towards self-peptides
- Function to suppress immune responses and maintain self-tolerance
- Secretes immunosuppressive cytokines e.g., TGF-B, IL-10
- Higher in cancer patients, recruited to tumours – associated with suppression of anti-tumour immunity and poor prognosis
What is the Intratumoral tertiary lymphoid structure (TLS)?
- TLS develop at sites of chronic inflammation in non-lymphoid tissues including tumours
- Act as a hub to recruit B and T lymphocytes
- Contains germinal centres – sites where B cells selected for antibody production
- Contains CD4+ T helper cells that provide CD40-CD40L help for B cell antibody production
- TLS strongest prognostic factor even in context of high or low cytotoxic T lymphocytes
- Strongly implies antibody is important for anti-tumour immunity
- Presence of TLS improves immunotherapy
What are natural killer cells?
- Expresses an array of ACTIVATING and INHIBITORY receptors:
o Activating: FcR (CD16), NKG2D and NKp44
o Inhibitory: bind to MHC-I e.g., KIR (human) - Activating receptors e.g., NKG2A generally binds to stress-inducible ligands on tumour cells e.g., MIC-A
- Important for catching tumour cells that downregulate MHC-I to evade CTL
- Presence in tumours is a good prognostic factor
- NK cells important for catching the cells that downregulate MHC-I to avoid the cytotoxic T cells
