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Pharm Decks > Lecture 7 - Cancer Immunotherapy > Flashcards

Lecture 7 - Cancer Immunotherapy Flashcards

1
Q

What specific factors on cancer cells are recognised by the immune system?

A

Neoantigens

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2
Q

What is self tolerance?

A

B and T cells against self antigens are discarded prior to maturation to avoid autoimmunity

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3
Q

How are T cells primed?

A

Primed by dendritic cells
Leads to their activation and maturation of T cells

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4
Q

How do tumour present neoantigens?

A
  • 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
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5
Q

What is cancer immunoediting and what are the 3 stages?

A
  • Cancer believed to recognised and removed by immunosurveillance
  1. Elimination
  2. Equilibrium
  3. Escape
  • Cancer immunoediting happens during cancer progression, but also in patients receiving anticancer immunotherapies
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6
Q

Overview of elimination stage of immunoediting

A
  • 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
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7
Q

What are natural killer cells and what is their function in elimination stage?

A
  • 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
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8
Q

What are the 3 main subsets of CD4+ cells?

A
  • Th1 cells
  • Th2 cells
  • Th17 cells
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9
Q

What do CD4+ Th1 cells do?

A
  • activated by IL-12
  • Release IFN-gamma, TNFalpha and IL-2
  • involved in macrophage activation
  • supresses Th2 responses
  • promote cell mediated cellular cytotoxicity
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10
Q

What do CD4+ Th2 cells do?

A
  • initiate B cells to produce antibodies
  • promote mast cell and eosinophil function
  • supresses Th1 responses (often called helper CD4 T cells)
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11
Q

What do CD4+ Th17 cells do?

A
  • secretes IL-17 –> promotes recruitment of neutrophiles
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12
Q

What are Cytotoxic T cells?

A
  • 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
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13
Q

What are the 3 main granules of cytotoxic T cells?

A

Perforin
Granzymes
Granulysin

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14
Q

What is the equilibrium stage of cancer immunoediting and what occurs?

A
  • 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
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15
Q

What occurs in the escape stage of cancer immunoediting?

A
  • 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
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16
Q

What surfaces molecules help tumours to ESCAPE from the immune system and therefore are upregulated during this process?

A
  • HLA-G / HLA-E
  • PD-L1/2
  • CD155 / CD112
  • CD47
  • CD39 / CD73
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17
Q

What are the features of CD8 T cell exhaustion in the escape stage of cancer immunoediting?

A
  • 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
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18
Q

What are the two groups of immune cells with regards to tumour growth/suppression?

A
  • Tumour promoting immune cells
  • Tumour supressing immune cells
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19
Q

Of the tumour promoting immune cells, what is the NORMAL function of Regulatory T cells?

A
  • 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).
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20
Q

Of the tumour promoting immune cells, what is the CANCEROUS function of Regulatory T cells?

A
  • In cancer, Tregs inhibit the antitumor immune response through inhibition of tumour-suppressing immune cells
21
Q

Of the tumour promoting immune cells, what is the cancerous function of Myeloid-derived suppressor cells?

A
  • 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
22
Q

What is a hot tumour?

A
  • 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
23
Q

What is a cold tumour?

A
  • 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
24
Q

What are examples of immunotherapy?

A
  • therapy which activates or relieves suppression of the immune system
  • Antibody therapy
  • Non-specific immune stimulation
  • Immune-checkpoint blockade
  • Adoptive cell transfer
25
Q

Overview of Non-specific Immune stimulation immunotherapy

A
  • 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)
26
Q

Examples of non-specific immune stimulation immunotherapy?

A
  • Examples include IL-2 and IFN-alpha which are used for kidney cancer and melanomas among other cancers.
27
Q

What is the function of IL-2?

A
  • Treg maintenance and function
  • T-cell proliferation and differentiation
28
Q

What is the function of IFNalpha?

A

Increases MHC I class expression

29
Q

Overview of monoclonal antibody therapies as an immunotherapy

A
  • 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
30
Q

What is the typical first line treatment for most cancers?

A
  • Chemotherapy
    Followed by a small amount of people receiving immunotherapy or targeted therapies
31
Q

Overview of CAR-T cell therapy as an immunotherapy?

A
  • 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
32
Q

What happens in complete response immunotherapy?

A
  • can drive tumours back to the elimination phase
33
Q

What happens in partial response immunotherapy?

A
  • fails to completely overcome tumour- induced immune suppression, the tumour might be forced into on- treatment equilibrium.
34
Q

What is acquired resistance to immunotherapy?

A
  • outgrowth of tumour cell clones capable of evading or suppressing anti-tumour immunity
  • result in secondary escape
35
Q

Overview of immune checkpoint blockade immunotherapy

A
  • 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
36
Q

What is an immune checkpoint?

A

regulators of the immune system for self-tolerance

37
Q

Examples of CTLA-4 ICIs?

A

Ipilimumab

38
Q

Examples of PD1 specific ICI?

A

Pembrolizumab
Nivolumab

39
Q

Will a hot or cold tumour respond better to ICI?

A

Hot

40
Q

What is a way a cancer will become resistant to immunotherpies?

A

Down regulate their ‘hotness’

41
Q

What is the main structures of a Chimeric Antigen Receptor?

A
  • 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
42
Q

What is the 2 in 1 benefit of CAR T cell therapy?

A
  • 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
43
Q

What receptor does CAR recognise on the tumours?

A

CD19

44
Q

How does CAR T kill tumours?

A
  • 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
45
Q

Limitations and issues with CAR T cell therapy (5 examples)

A
  • 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
46
Q

How can we make a tumour hot?

A
  • 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
47
Q

What is the role of M1 macrophage?

A
  • tumour suppressing immune cell
  • Pro-inflammatory
  • release IL-12, TNF-a, IL-1
  • antigen presentation capacity
  • Th1 response
48
Q

What is the role of an M2 macrophage?

A
  • 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

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