28 Cancer Immunology II Flashcards
NAME 3 lines of evidence for immune SURVEILLANCE
- Immunosuppressed patients = INC tumors
- Nude mice
- RAG-/- mice
WHY do immunosuppressed patients show INC tumor?
“ACCEPT” tumors
What is special about NUDE mice
No thymus
Are nude mice a good model of immunedeficiency?
Explain
NO
- Has functional T-cells
- Has more NK cells than normal mice
What is RAG2
Lymphocyte genetic RESHUFFLING gene
What happens in RAG2-/- mice?
100% TUMOR development
Define immunoediting
Immune system driving expansion of tumors
What are the 3 E’s of immunoediting?
Elimination
Equilibrium
Escape
What happens in the elimination step
Immune cells DESTROY cancer cells 😃
only have some mutations = slightly immunogenic
What happens in the EQUILIBRIM stage
Some cells undergo FURTHER mutation
= RESISTANT to immune killing 😭
(Immune system selects FOR resistance)
What happens in the ESCAPE stage
EXPANSION of immune-RESISTANT cells (highly mutated)
Acronym for the ESCAPE mechanisms in tumor cells?
List these
HCTI “Hiding” Counterattack T-cell dysfuncion Immunosuppression
NAME 2 ways of “hiding” from immune system
- MHCI down-reg or KO
* NK killing evasion
Function of normal MHCI?
What binds to MHCI?
ALL cells present proteome antigens on MHCI
LYMPHOCYTES perform immune surverillance
What is the EFFECT of KO MHCI
No MHCI = no antigen presentation = NO CD8 cytotoxic T-cell killing
2 ways in which tumor cells EVADE NK cell killing?
Secreting INHIBITORY signals (TGFβ, PGE2) = ⬇️NK RECEPTORS
Down-reg co-stimulatory B7 = ⬇️NK ACTIVITY
What happens in MELANOMA with INC B7 activity?
INC B7 = INC NK activity = tumor free!!
What is B7
Co-stimulatory molecule for NK cells
3 ways in which tumor cells perform COUNTERATTACK
- CHECKPOINT inhibition
- APOPTOTIC escape
- Fas-pathway KILLING
How do cancer cells inhibit immune CHECKPOINTS
Cancer cells have PD-L1 (finger), which binds T-cell PD1 (button)
= INHIBIT T-cell signalling
= APOPTOSIS
How do cancer cells EVADE apoptosis?
Down-regualte apoptotic PROTEINS
In the Fas pathway, which cell DIES?
- cell with Fas-R
- cell with Fas-L
Cell with Fas-R will die
How do cancer cells kill T-cells via FAS pathway?
Fas-L (cancer cells) binds Fas-R (CTLs)
= counterattack to KILL CTLs
How does HIGH CD8 T-cell infiltration usually affect PROGNOSIS?
BETTER prognosis
2 ways tumor cells cause T-cells DYSFUNCTION
- Impair T-cell SIGNALLING
* Impair NF-kB signalling
How do tumor cells impair T-cell SIGNALLING?
Tumor secretes factors to ∆signal transduction
Is the ∆signal transduction in T-cells reversible?
Explain
Usually reversible if:
- T-cell REMOVED from tumor microenvironment
- EXCISION of tumor
Where does impaired T-cell signalling BEGIN?
How does it progress?
Begins AT tumor site
Spreads to PERIPHERAL T-cells
Why does impaired NF-kB signalling cause T-cell dysfunctin
NF-kB is a TF that inducdes many IMMUNE GENES
Name 2 Tx approches to REPLACE T-cells
- Transplant cells
2. “Designer” T-cells
In a mouse study, lymphocytes to be transplanted were cultured with WHAT factor?
Why?
Lymphocytes from HEALTHY mice cultured with IL-2 (induces proliferation)
What happened when lymphocytes from HEALTHY mice were transplanted to the cancerous mouse?
CURED tumors in mice!
Is this transplant method viable in HUMANS?
Only works in 10% of human patients…
Name the TYPE of “designer” T-cell
CAR T-cells
= Chimeric Antigen Receptor
What are the components of a CAR
Antibody variable region
TcR
Benefits of a CAR lymphocyte?
INDEPENDENT antigen recognition = POTENT
does not require MHC or additional co-stimulation!
2 PATHWAYS to cause immunosuppression?
Cellular
Soluble
Name the 3 cellular methods of inducing immunosuppression
Treg
MDSCs
TAMs
How can tumor cells use Treg cells to cause immunosuppresion?
Promote maturation of NAIVE Treg cells
OR
Directly stimulate MATURE Treg cells
What are MDSCs
Myeloid-Derived Stem Cells
Function of MDSCs
Same as Treg (also suppresses T-cell function)
3 things secreted by MDSCs
O2 radicals
Arginase 1
iNOS
What does Arginase-1 from MDSCs do?
Depletes L-Arginine (needed by T-cells)
What does iNOS do?
Inducible NO synthase = makes NO
What happens to the NO made by MDSCs?
NO combines with O2 radicals
= peroxynitrite
How do MDSCs use peroxynitrite to kill T-cells?
MDSCs present antigens to T-cells
Release TOXIC peroxynitrite = KILL T-cells
TAM infiltration = _____ prognosis
BAD prognosis
What are the 2 PHENOTYPES of macrophages?
How does this CHANGE in tumors?
M1 = ANTI-tumor M2 = PRO-tumor
Tumors covnert TAMS to M2 phenotype
Name PRO-tumor functions of M2 macrophages
- Invasion (proteases)
- Angiogenesis
- Proliferation
- Immunosuppression
What factors are secreted by M2 macrophages to cause immunosuppression?
PD-L1
IDO1
IL10 (induces Treg cells)
What is a SOLUBLE immunosuppression method?
IDO1
Name 2 PHYSIOLOGICAL functions of IDO1
- INFLAMMATION = normal immunosuppression to allow HEALING
* PREGNANCY = immune TOLERANCE of baby
What metabolic PATHWAY is IDO1 part of?
KP = Kyurenine pathway
What does INC IDO1 in cancer lead to?
Promote Kyurenine pathway
= 95% Tryptophan (W) depletion
= accumulation of W metabolites
= T-cell APOPTOSIS
What is the “Double Trouble” effect caused by KP?
DEC Tryptophan
INC Kyurenine
How does the “Double Trouble” effect cause immunosuppresion
DIRECTLY and INDIRECTLY
Directly suppress T/NK cells
Indirectly suppress T/NK cells via ⬆️Treg
HIGH IDO1 + Kyurenine = ______ prognosis
POOR prognosis
What 2 drug types used in COMBO Tx gives better outcome?
Checkpoint-inhibitor (anti-PD-L1)
IDO1-inhibitor
Works better as COMBO than alone
