Lecture 7 - Cancer Immunotherapy Flashcards
What specific factors on cancer cells are recognised by the immune system?
Neoantigens
What is self tolerance?
B and T cells against self antigens are discarded prior to maturation to avoid autoimmunity
How are T cells primed?
Primed by dendritic cells
Leads to their activation and maturation of T cells
How do tumour present neoantigens?
- abnormal proteins which are broken up into peptides
- displayed on the surface of the cancer cell
- perceived as “non-self” and generate an immune response
- Neo-antigens presented by MHC on cell surface
- Detection by T-cells eliminates cancerous cells
What is cancer immunoediting and what are the 3 stages?
- Cancer believed to recognised and removed by immunosurveillance
- Elimination
- Equilibrium
- Escape
- Cancer immunoediting happens during cancer progression, but also in patients receiving anticancer immunotherapies
Overview of elimination stage of immunoediting
- innate and adaptive immune responses to tumours
- Macrophages, natural killer (NK) and NKT cells recognise and kill cancer cells
- T-cells and antibodies (B-cells) recognise tumour-associated antigens, CD8 cytotoxic T cells
What are natural killer cells and what is their function in elimination stage?
- first line of defence
- produce IFN-gamma
- direct cytotoxic activity against
- inhibited by ligands on healthy cells –> bind to inhibitory receptors on NK cells
- up-regulation of stress-induced ligands in tumour cells –> NK cell activation
What are the 3 main subsets of CD4+ cells?
- Th1 cells
- Th2 cells
- Th17 cells
What do CD4+ Th1 cells do?
- activated by IL-12
- Release IFN-gamma, TNFalpha and IL-2
- involved in macrophage activation
- supresses Th2 responses
- promote cell mediated cellular cytotoxicity
What do CD4+ Th2 cells do?
- initiate B cells to produce antibodies
- promote mast cell and eosinophil function
- supresses Th1 responses (often called helper CD4 T cells)
What do CD4+ Th17 cells do?
- secretes IL-17 –> promotes recruitment of neutrophiles
What are Cytotoxic T cells?
- CD8+
- induce cell killing
- Need priming with dendritic cells
- Release diff factors
- Break holes into the membrane of target cell and sort of lyse the cells
- However need the interaction between T and cancer cells for this to happen
What are the 3 main granules of cytotoxic T cells?
Perforin
Granzymes
Granulysin
What is the equilibrium stage of cancer immunoediting and what occurs?
- Rare tumour subclones with further mutations survive elimination
- Tumour progresses into the equilibrium phase
- selection pressures instigate new tumour cell genetic variants (genetic instability and/or immune selection)
- Net tumour growth is limited and can be stalled
What occurs in the escape stage of cancer immunoediting?
- select for tumour subclones with reduced immunogenicity that can evade immune recognition and destruction
- e.g. decrease in IFNg secretion
- tumour cells gain characteristics which allow them to hide from immune system
What surfaces molecules help tumours to ESCAPE from the immune system and therefore are upregulated during this process?
- HLA-G / HLA-E
- PD-L1/2
- CD155 / CD112
- CD47
- CD39 / CD73
What are the features of CD8 T cell exhaustion in the escape stage of cancer immunoediting?
- exhausted phenotype
- reduced expression of activating receptors
- Increase in PDL1 expression on tumour cells
- Failure to produce tumour neoantigens
- Mutations in MHC genes —> loss of MHC complex
- Increased release of immune suppressive factors
e.g. TGFb which inhibit T-cell activation - Increased number of immunosuppressive cell types= tumour promoting
What are the two groups of immune cells with regards to tumour growth/suppression?
- Tumour promoting immune cells
- Tumour supressing immune cells
Of the tumour promoting immune cells, what is the NORMAL function of Regulatory T cells?
- subset of CD4+ T cells
- immunosuppressive properties –> maintaining immune homeostasis and self-tolerance, limiting excessive inflammation, and preventing autoimmunity.
- inhibit immune cell types including CD8+and CD4+effector T cells, natural killer (NK) cells, and dendritic cells (under normal conditions to restore homeostasis following inflammation).
Of the tumour promoting immune cells, what is the CANCEROUS function of Regulatory T cells?
- In cancer, Tregs inhibit the antitumor immune response through inhibition of tumour-suppressing immune cells
Of the tumour promoting immune cells, what is the cancerous function of Myeloid-derived suppressor cells?
- immunosuppressive
- inhibit NK cells, CD8+ and CD4+ effector T cells
- promote expansion of regulatory T cells.
- produce IL-10, TGF-beta and other cytokines
- Produce ROS and RNS
What is a hot tumour?
- enriched with immune active cells – like T cells, M1 macrophages
- high mutational load
- high levels of neoantigens –> recognized by immune system
- Lot of immune cells in the TME
What is a cold tumour?
- lack T cells within the tumour tissue and the TME
- ‘immune cell-excluded’ tumours –> T cells in surrounding stroma but not in tumour tissue
- don’t respond well to immunotherapy
What are examples of immunotherapy?
- therapy which activates or relieves suppression of the immune system
- Antibody therapy
- Non-specific immune stimulation
- Immune-checkpoint blockade
- Adoptive cell transfer
Overview of Non-specific Immune stimulation immunotherapy
- Does not directly target cancer cells
- stimulates patients immune response in a general way to kill tumour cells
- often used in combination with other treatments (adjuvant)
Examples of non-specific immune stimulation immunotherapy?
- Examples include IL-2 and IFN-alpha which are used for kidney cancer and melanomas among other cancers.
What is the function of IL-2?
- Treg maintenance and function
- T-cell proliferation and differentiation
What is the function of IFNalpha?
Increases MHC I class expression
Overview of monoclonal antibody therapies as an immunotherapy
- mAb may bind to receptors
- may prevent dimerization of receptor
- attract other immune cells
- may be linked to toxin
- some bi-specific, bind one side to tumour cell and other T cell
What is the typical first line treatment for most cancers?
- Chemotherapy
Followed by a small amount of people receiving immunotherapy or targeted therapies
Overview of CAR-T cell therapy as an immunotherapy?
- Remove patients T cells
- Genetically modify the T cell so it overexpresses the Chimeric Antigen Receptor to help it target the tumour cells better
- Precondition with high dose chemotherapy (irradicate the immune system) don’t have an attack of the injected T cells and allows the T cells to expand better
What happens in complete response immunotherapy?
- can drive tumours back to the elimination phase
What happens in partial response immunotherapy?
- fails to completely overcome tumour- induced immune suppression, the tumour might be forced into on- treatment equilibrium.
What is acquired resistance to immunotherapy?
- outgrowth of tumour cell clones capable of evading or suppressing anti-tumour immunity
- result in secondary escape
Overview of immune checkpoint blockade immunotherapy
- Tumours can overexpress receptors such as PD-L1 which signals to T cells not to kill them
- Immune checkpoint inhibitors interrupt this interaction so that the T cells are not inhibited and can detect and kill the cancer
What is an immune checkpoint?
regulators of the immune system for self-tolerance
Examples of CTLA-4 ICIs?
Ipilimumab
Examples of PD1 specific ICI?
Pembrolizumab
Nivolumab
Will a hot or cold tumour respond better to ICI?
Hot
What is a way a cancer will become resistant to immunotherpies?
Down regulate their ‘hotness’
What is the main structures of a Chimeric Antigen Receptor?
- single-chain variable fragment (scFv) of an antibody, which provides target specificity
- Hinge and transmembrane region
- a co-stimulatory domain; and a T-cell-activation domain
What is the 2 in 1 benefit of CAR T cell therapy?
- One receptor contains the T cell receptor signal and a costimulatory receptor (cloned within the same receptor)
- The signal through this one receptor is sufficient
What receptor does CAR recognise on the tumours?
CD19
How does CAR T kill tumours?
- CAR-T cells recognise and bind with ScFv region to tumour cells
- Binding causes intercellular signalling in CAR-T cells
- Activation of CAR-T cell and rapid proliferation
- CAR-T cells attack and kill cancer cells
Limitations and issues with CAR T cell therapy (5 examples)
- need to expand T cells, need to grow outside body, inject back in and survive in the patient
- immunosuppressive TME –> they might not survive
- tumour cells might downregulate CD19 so won’t be recognised by CAR
- CAR-T can induce systemic inflammation (toxicities)
- Most only work against B cell lymphoma and ALL, none in solid tumours
How can we make a tumour hot?
- Improve the T cell priming via use of chemo or radiotherapy which will kill the tumours and release neoantigens
- Expand T cells
- T cell trafficking, thinking how can we inhibit cells which produce stromal barriers around the cancer cells
What is the role of M1 macrophage?
- tumour suppressing immune cell
- Pro-inflammatory
- release IL-12, TNF-a, IL-1
- antigen presentation capacity
- Th1 response
What is the role of an M2 macrophage?
- Tumour promoting immune cell
- tumour associated macrophage
- support an environment which helps tumours
- release growth factors
- inactivate T cells
- anti-inflammatory
- produce cytokines IL-10 and TGF-beta
