Final Content - week 8 Flashcards
What’s B7?
Where is it located?
A ligand
On APC
What’s CD28?
Where is it located?
A receptor protein
On CD8+
Whats MHC-1?
Where is it located?
A precenter molecule
On APC
What’s TCR?
Where is it located?
T-cell receptor
On CD8+
What’s CTLA-4?
Where is it located?
A receptor protein
On CD8+
CD8+ activation pathway: mechanism 1
B7 - CD28 binding
CD8+ activation pathway: mechanism 2
MHC1 - Antigen - TCR binding
What happens upon CD8+ activation?
CD8+ T cells become cytotoxic T lymphocytes (CTLs), killing antigen of interest via cellular attack
CD8+ inhibition pathway: mechanism 1
MHC1 - Antigen - TCR and B7 - CTLA4 binding
CD8+ inhibition pathway: mechanism 2
in which cell is the receptor present? the ligand?
PD-1R / PD-Ligand binding
PD1R located on the T-cell
PDL located on APCs or target cells
What happens upon CD8+ inactivation?
There will be no cellular attack
Is CD8+ inhibition a good thing?
Generally, yes. Inhibition pathways, also known as immune checkpoints, are there to inhibit autoimmunity
What’s autoimmunity?
immune system attacking healthy tissues
Are CD8+ activation and inactivation both immune checkpoints?
No, only CD8+ inactivation
What are TATA/TSTA?
Tumor antigens w/ immune response
what is immunogenic?
what are some examples?
capable of triggering immune response
e.g. TATA/TSTA
What are immunogenic tumor antigens?
molecules found on cancer cells that immune system recognizes to target cells for its death
Explain the hallmark - avoidance of immune destruction
cancer avoiding immune system
Hallmark - Avoidance of immune destruction: down regulation of tumor antigens.
Explain:
(a) what this means
(b) how is this accomplished
(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
Hallmark - Avoidance of immune destruction: Avoids by down regulating MHC-1 expression
Explain:
(a) what this means
(b) how is this accomplished
(a) MHC-1 is not properly displayed on cell membrane
(b) cancer cells lose proteins that usually drive MHC1 onto the membrane
Hallmark - Avoidance of immune destruction: decrease stress signals
Explain:
(a) what this means
(b) how is this accomplished
(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
If cancer cells aren’t killed by CD8+ T cells, what else has the ability to kill cancer cells?
NK cells (Natural Killer cell)
What is the difference between healthy MICB/A cells and decoy MICB/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
Hallmark - Avoidance of immune destruction: decrease apoptosis
“don’t kill me”
Explain:
(a) what this means
(b) how is this accomplished
(a) apoptosis - programed cell death - is decreased
(b) there is a decrease in the FASR - FASL binding in FAS mediated apoptosis. IAPS will increase
what does IAPs stand for?
Inhibitors of Apoptosis Proteins
Hallmark - Avoidance of immune destruction: cancer counteracts
“I’ll kill you instead”
Explain:
(a) what this means
(b) how is this accomplished
(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
- increase in PD1R on tumor cell - decreases effectiveness of cancer cell apoptosis
- release cytotoxins to inhibit + kill T-cells via attraction and activation of TREGs
What’s TREGs?
- TREGs stand for Regulatory T cells
- They are a type of immune cell
- suppress the immune response
–>global inhibitor of the immune response
Is TREGs good or bad in terms of cancer?
Bad: tumors can exploit TREGs to evade immune attack.
PAP is common in what type of cancer?
Prostate cancer
Therapeutics - passive immunity. Explain what it means
introducing antibodies or immune cells from another source
what is ADCC - Antibody-Dependent Cellular Cytotoxicity?
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
Immunology therapeutics: Vectibix
EGFR antibody against colorectal cancer
–> monoclonal antibody
–> induce ADCC against CC
Immunology therapeutics: Herceptin
HER2-R antibody against breast cancer
–> monoclonal antibody
–> induce ADCC against CC
Immunology therapeutics: Avastin
Anti-VEGF (decreases angiogenesis)
–> monoclonal antibody
–> induce ADCC against CC
Immunology therapeutics: Rituxan
D20 antigen antibody (B-cell cancers, non-hodgkins lymphoma)
–> monoclonal antibody
–> induce ADCC against CC
Immune checkpoint therapeutics: Yervoy
(a) antibody blocking CTLA-4 checkpoint
(b) increases cytotoxic T cell activation
Immune checkpoint therapeutics: Keytruda
(a) antibody blocking PD-1 checkpoint
(b) increases cytotoxic T cell killing
what are immune checkpoint co-stimulatory/inhibitory molecules involved in?
in regulating T cell activation
Oncolytic virus therapeutics: T-vec
(a) oncolytic virus - modified herpes simplex virus that selectively infects and kills cancer cells
(b) only replicates in cancer cells
Direct Killing -
explain the prupose/mechanism.
an immune system’s way of eliminating abnormal cells via cell-to-cell contact
what are some examples of cells that kill via direct mechanism?
Cytotoxic T lymphocytes (CTLs)
Natural Killer (NK) cells:
Systematic Killing - an immune system’s way of eliminating abnormal cells.
explain the mechanism
immune system launches a larger, coordinated attack against abnormal cells
–>It doesn’t rely on direct cell-to-cell contact.
what are some examples of cells that kill via systematic mechanism?
Antibody-dependent cellular cytotoxicity (ADCC)
Cytokines
Therapeutic vaccines: provenge
(a) Adoptive cell therapy
(b) FDA approved therapeutic vaccine for metastatic prostate cancer
how does provenge work?
(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
Therapeutic vaccines: CAR-T cells
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
CAR-T cell adjustment 1
problem and solution
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
CAR-T cell adjustment 2
problem and solution
problem: CAR-T cells can cause autoimmunity
solution: adding self activating domains to CAR-T cells such that they can self activate
CAR-T cell adjustment 3
problem and solution
problem: CAR-T cells might not be as effective
solution: increase co-stimulatory molecules (CD28) expressed on cell surface
What is a way in which cancer cells are able to evade CAR-T cells even after modifications?
the tumor cell removes antigens given that antigens can be recognized even without MHC1
What is another way in which cancer cells are able to evade CAR-T cells even after modifications?
T-cell exhaustion via cancer cells releasing PDL into extracellular fluid.
CAR-T cells will bind PDL @ a higher frequency which deactivates T-cells
Can CAR-T cells fight cancer adjustments? how?
yes, by further modification
Whats a further modification used to fight cancer adjustments?
CAR-T cell’s native receptor, PD1, is removed
4th gen CAR-T cells - TRUCKS
(a) modification?
(b) why?
(a) modification: added production of immuno-stimulating molecules
(b) to increase T cell activity and decrease TREG activity
5th gen CAR-T cells
(a) modification?
(b) why?
(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
what are the current problems with ex-vivo production of car-t cells?
(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
what are some future CAR-T cell therapies?
Addition of NK signals Combinatorial therapies using
–>Immune checkpoint blockers
–>VEGF antibodies
–>Different antigens
Hallmark of cancer: angiogenesis
explain
Formation of new capillaries - the smallest blood vessels in your body - from current vessels; tightly regulated
explain the early process of angiogenesis. a - d
(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.
Normal angiogenesis process - 4 total
- embryonic development
- wound healing
- menstruation
- growth
Pathological angiogenesis - 3 total
- psoriasis
- diabetic retinopathy
- cancer
angiogenic therapeutics - 4 total
- heart attacks
- natural damage
- bone healing
- blood flow
tumor angiogenesis: What is the rate limiting step in tumor growth?
Nutrients & oxygen
tumor angiogenesis: How large can a tumor grow with limited blood supply?
1-2mm
tumor angiogenesis: What process do tumors go through to solve this problem?
angiogenesis
ANGIOGENIC SWITCH: What characterizes angiogenic
vasculature in tumors? 4 total
- Disorganization, leaks, improper cell junctions - Caused by an excess of positive factors
- Poorly associated pericytes
–> Pericytes: support cells for vasculature, tightly associated with basement layer - Lack of vessel-type distinctions
–> Capillaries vs. venules vs. arterioles - Holes to the basement layer - Lack of endothelial cells; not forming a distinct layer
ANGIOGENIC SWITCH: What triggers an angiogenic switch? 3 total
- Activation of oncogenes
ex. RAS/MAPK pathway - Down-regulation of tumor suppressors
ex. p53 - Environmental cues
ex. hypoxia
whats HIF-Alpha?
Hypoxia-Inducible Factor-alpha - a protein that plays a critical role in the body’s response to low oxygen levels (hypoxia
explain HIF-Alpha w/ oxygen
Hif-a will associate w/ VHL protein to target it for degradation which results in no VEGF production
explain HIF-Alpha w/o oxygen - hypoxic state
hif-a translocates into nucleus and beings VEGF transcription
