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BIMM 134 - Cancer > Final Content - week 8 > Flashcards

Final Content - week 8 Flashcards

1
Q

What’s B7?
Where is it located?

A

A ligand
On APC

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2
Q

What’s CD28?
Where is it located?

A

A receptor protein
On CD8+

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3
Q

Whats MHC-1?
Where is it located?

A

A precenter molecule
On APC

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4
Q

What’s TCR?
Where is it located?

A

T-cell receptor
On CD8+

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5
Q

What’s CTLA-4?
Where is it located?

A

A receptor protein
On CD8+

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6
Q

CD8+ activation pathway: mechanism 1

A

B7 - CD28 binding

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7
Q

CD8+ activation pathway: mechanism 2

A

MHC1 - Antigen - TCR binding

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8
Q

What happens upon CD8+ activation?

A

CD8+ T cells become cytotoxic T lymphocytes (CTLs), killing antigen of interest via cellular attack

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9
Q

CD8+ inhibition pathway: mechanism 1

A

MHC1 - Antigen - TCR and B7 - CTLA4 binding

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10
Q

CD8+ inhibition pathway: mechanism 2

in which cell is the receptor present? the ligand?

A

PD-1R / PD-Ligand binding

PD1R located on the T-cell
PDL located on APCs or target cells

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11
Q

What happens upon CD8+ inactivation?

A

There will be no cellular attack

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12
Q

Is CD8+ inhibition a good thing?

A

Generally, yes. Inhibition pathways, also known as immune checkpoints, are there to inhibit autoimmunity

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13
Q

What’s autoimmunity?

A

immune system attacking healthy tissues

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14
Q

Are CD8+ activation and inactivation both immune checkpoints?

A

No, only CD8+ inactivation

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15
Q

What are TATA/TSTA?

A

Tumor antigens w/ immune response

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16
Q

what is immunogenic?
what are some examples?

A

capable of triggering immune response
e.g. TATA/TSTA

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17
Q

What are immunogenic tumor antigens?

A

molecules found on cancer cells that immune system recognizes to target cells for its death

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18
Q

Explain the hallmark - avoidance of immune destruction

A

cancer avoiding immune system

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19
Q

Hallmark - Avoidance of immune destruction: down regulation of tumor antigens.

Explain:
(a) what this means
(b) how is this accomplished

A

(a) cancer can hide its identity such that CD8+ T-cells cannot detect it

(b) Cancer undergoes immuno editing to remove non-critical functional antigens

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20
Q

Hallmark - Avoidance of immune destruction: Avoids by down regulating MHC-1 expression

Explain:
(a) what this means
(b) how is this accomplished

A

(a) MHC-1 is not properly displayed on cell membrane

(b) cancer cells lose proteins that usually drive MHC1 onto the membrane

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21
Q

Hallmark - Avoidance of immune destruction: decrease stress signals

Explain:
(a) what this means
(b) how is this accomplished

A

(a) there is a decrease in MHC1 cells so that neither T or NK cells kill cancer

(b) decoy MICB/MICA bind to NKG2D receptor on NK cells
–> healthy MICB/MICA remain in cancer cells but do NOT interact w/ NK cells

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22
Q

If cancer cells aren’t killed by CD8+ T cells, what else has the ability to kill cancer cells?

A

NK cells (Natural Killer cell)

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23
Q

What is the difference between healthy MICB/A cells and decoy MICB/A?

A

healthy = located on cell surface and signal NK cell activation

decoy = secreted from cancer cells and act as deceptive molecules, preventing NK cell activation

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24
Q

Hallmark - Avoidance of immune destruction: decrease apoptosis

“don’t kill me”

Explain:
(a) what this means
(b) how is this accomplished

A

(a) apoptosis - programed cell death - is decreased

(b) there is a decrease in the FASR - FASL binding in FAS mediated apoptosis. IAPS will increase

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25
Q

what does IAPs stand for?

A

Inhibitors of Apoptosis Proteins

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26
Q

Hallmark - Avoidance of immune destruction: cancer counteracts

“I’ll kill you instead”

Explain:
(a) what this means
(b) how is this accomplished

A

(a) cancer kills healthy cells instead

(b) 1. tumor cells release soluble FASL that bind T-cell FASR (t-cell receptor), inducing FAS mediated apoptosis in T-cells

  1. increase in PD1R on tumor cell - decreases effectiveness of cancer cell apoptosis
  2. release cytotoxins to inhibit + kill T-cells via attraction and activation of TREGs
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27
Q

What’s TREGs?

A
  • TREGs stand for Regulatory T cells
  • They are a type of immune cell
  • suppress the immune response

–>global inhibitor of the immune response

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28
Q

Is TREGs good or bad in terms of cancer?

A

Bad: tumors can exploit TREGs to evade immune attack.

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29
Q

PAP is common in what type of cancer?

A

Prostate cancer

30
Q

Therapeutics - passive immunity. Explain what it means

A

introducing antibodies or immune cells from another source

31
Q

what is ADCC - Antibody-Dependent Cellular Cytotoxicity?

A

attack innate immune cells such that they do NOT need a specific antigen for immune response

–> process where cells destroy target cells that are coated w/ antibodies

32
Q

Immunology therapeutics: Vectibix

A

EGFR antibody against colorectal cancer

–> monoclonal antibody
–> induce ADCC against CC

33
Q

Immunology therapeutics: Herceptin

A

HER2-R antibody against breast cancer

–> monoclonal antibody
–> induce ADCC against CC

34
Q

Immunology therapeutics: Avastin

A

Anti-VEGF (decreases angiogenesis)

–> monoclonal antibody
–> induce ADCC against CC

35
Q

Immunology therapeutics: Rituxan

A

D20 antigen antibody (B-cell cancers, non-hodgkins lymphoma)

–> monoclonal antibody
–> induce ADCC against CC

36
Q

Immune checkpoint therapeutics: Yervoy

A

(a) antibody blocking CTLA-4 checkpoint

(b) increases cytotoxic T cell activation

37
Q

Immune checkpoint therapeutics: Keytruda

A

(a) antibody blocking PD-1 checkpoint

(b) increases cytotoxic T cell killing

38
Q

what are immune checkpoint co-stimulatory/inhibitory molecules involved in?

A

in regulating T cell activation

39
Q

Oncolytic virus therapeutics: T-vec

A

(a) oncolytic virus - modified herpes simplex virus that selectively infects and kills cancer cells

(b) only replicates in cancer cells

40
Q

Direct Killing -
explain the prupose/mechanism.

A

an immune system’s way of eliminating abnormal cells via cell-to-cell contact

41
Q

what are some examples of cells that kill via direct mechanism?

A

Cytotoxic T lymphocytes (CTLs)

Natural Killer (NK) cells:

42
Q

Systematic Killing - an immune system’s way of eliminating abnormal cells.

explain the mechanism

A

immune system launches a larger, coordinated attack against abnormal cells

–>It doesn’t rely on direct cell-to-cell contact.

43
Q

what are some examples of cells that kill via systematic mechanism?

A

Antibody-dependent cellular cytotoxicity (ADCC)

Cytokines

44
Q

Therapeutic vaccines: provenge

A

(a) Adoptive cell therapy

(b) FDA approved therapeutic vaccine for metastatic prostate cancer

45
Q

how does provenge work?

A

(a) uses body’s immune cells to fight cancer

(b) results in stronger immune cells that are able to fight cancer

–> essentially boosts and amplifies immune cells via provenge

46
Q

Therapeutic vaccines: CAR-T cells

A

Patiens own t-cells removed via blood and undergo genetic modifications which results in better t-cells

–> injected back into patient and won’t be rejected bc its their own cells

47
Q

CAR-T cell adjustment 1

problem and solution

A

problem: tumors down regulate MHC-1

solution: Cells are modified to gain the ability of recognizing an antibody located on the tumor surface w/o the need of MHC-1

48
Q

CAR-T cell adjustment 2

problem and solution

A

problem: CAR-T cells can cause autoimmunity

solution: adding self activating domains to CAR-T cells such that they can self activate

49
Q

CAR-T cell adjustment 3

problem and solution

A

problem: CAR-T cells might not be as effective

solution: increase co-stimulatory molecules (CD28) expressed on cell surface

50
Q

What is a way in which cancer cells are able to evade CAR-T cells even after modifications?

A

the tumor cell removes antigens given that antigens can be recognized even without MHC1

51
Q

What is another way in which cancer cells are able to evade CAR-T cells even after modifications?

A

T-cell exhaustion via cancer cells releasing PDL into extracellular fluid.

CAR-T cells will bind PDL @ a higher frequency which deactivates T-cells

52
Q

Can CAR-T cells fight cancer adjustments? how?

A

yes, by further modification

53
Q

Whats a further modification used to fight cancer adjustments?

A

CAR-T cell’s native receptor, PD1, is removed

54
Q

4th gen CAR-T cells - TRUCKS

(a) modification?

(b) why?

A

(a) modification: added production of immuno-stimulating molecules

(b) to increase T cell activity and decrease TREG activity

55
Q

5th gen CAR-T cells

(a) modification?

(b) why?

A

(a) removed self activating domain and instead, activation is tied to antigen binding

(b) to minimize off-target effects of car-t cells as too much co-stimulatory domains can potentially attack cells outside of cancer

56
Q

what are the current problems with ex-vivo production of car-t cells?

A

(a) excessive immune response - cytokine release syndrome (CRS) - overactive immune system can hurt us

(b) Parkinsons-like symptoms in CAR-T cell patients - Immune Effector Cell-Associated Neurotoxicity - in repose to overactive CAR-T cells

57
Q

what are some future CAR-T cell therapies?

A

Addition of NK signals Combinatorial therapies using
–>Immune checkpoint blockers
–>VEGF antibodies
–>Different antigens

58
Q

Hallmark of cancer: angiogenesis

explain

A

Formation of new capillaries - the smallest blood vessels in your body - from current vessels; tightly regulated

59
Q

explain the early process of angiogenesis. a - d

A

(a) cell proliferation - rapid and uncontrolled division - releases growth factors such as VEGF/EGF via RAS/PI3K pathway

(b) matrix degradation occurs - degradation relies on proteases

(c) cancer cells begin migration away from main tumor - relies on EMT (epithelial-mesenchymal transition) to increase motility

(d) re-establishment - restoring blood flow and nutrient supply to the growing tumor.

60
Q

Normal angiogenesis process - 4 total

A
  1. embryonic development
  2. wound healing
  3. menstruation
  4. growth
61
Q

Pathological angiogenesis - 3 total

A
  1. psoriasis
  2. diabetic retinopathy
  3. cancer
62
Q

angiogenic therapeutics - 4 total

A
  1. heart attacks
  2. natural damage
  3. bone healing
  4. blood flow
63
Q

tumor angiogenesis: What is the rate limiting step in tumor growth?

A

Nutrients & oxygen

64
Q

tumor angiogenesis: How large can a tumor grow with limited blood supply?

A

1-2mm

65
Q

tumor angiogenesis: What process do tumors go through to solve this problem?

A

angiogenesis

66
Q

ANGIOGENIC SWITCH: What characterizes angiogenic
vasculature in tumors? 4 total

A
  1. Disorganization, leaks, improper cell junctions - Caused by an excess of positive factors
  2. Poorly associated pericytes
    –> Pericytes: support cells for vasculature, tightly associated with basement layer
  3. Lack of vessel-type distinctions
    –> Capillaries vs. venules vs. arterioles
  4. Holes to the basement layer - Lack of endothelial cells; not forming a distinct layer
67
Q

ANGIOGENIC SWITCH: What triggers an angiogenic switch? 3 total

A
  1. Activation of oncogenes
    ex. RAS/MAPK pathway
  2. Down-regulation of tumor suppressors
    ex. p53
  3. Environmental cues
    ex. hypoxia
68
Q

whats HIF-Alpha?

A

Hypoxia-Inducible Factor-alpha - a protein that plays a critical role in the body’s response to low oxygen levels (hypoxia

69
Q

explain HIF-Alpha w/ oxygen

A

Hif-a will associate w/ VHL protein to target it for degradation which results in no VEGF production

70
Q

explain HIF-Alpha w/o oxygen - hypoxic state

A

hif-a translocates into nucleus and beings VEGF transcription

BIMM 134 - Cancer (4 decks)

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