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MEDSCI302 > 28 Cancer Immunology II > Flashcards

28 Cancer Immunology II Flashcards

1
Q

NAME 3 lines of evidence for immune SURVEILLANCE

A
  • Immunosuppressed patients = INC tumors
  • Nude mice
  • RAG-/- mice
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2
Q

WHY do immunosuppressed patients show INC tumor?

A

“ACCEPT” tumors

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3
Q

What is special about NUDE mice

A

No thymus

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4
Q

Are nude mice a good model of immunedeficiency?

Explain

A

NO

  • Has functional T-cells
  • Has more NK cells than normal mice
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5
Q

What is RAG2

A

Lymphocyte genetic RESHUFFLING gene

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6
Q

What happens in RAG2-/- mice?

A

100% TUMOR development

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7
Q

Define immunoediting

A

Immune system driving expansion of tumors

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8
Q

What are the 3 E’s of immunoediting?

A

Elimination
Equilibrium
Escape

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9
Q

What happens in the elimination step

A

Immune cells DESTROY cancer cells 😃

only have some mutations = slightly immunogenic

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10
Q

What happens in the EQUILIBRIM stage

A

Some cells undergo FURTHER mutation
= RESISTANT to immune killing 😭
(Immune system selects FOR resistance)

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11
Q

What happens in the ESCAPE stage

A

EXPANSION of immune-RESISTANT cells (highly mutated)

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12
Q

Acronym for the ESCAPE mechanisms in tumor cells?

List these

A 
HCTI
“Hiding”
Counterattack
T-cell dysfuncion
Immunosuppression
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13
Q

NAME 2 ways of “hiding” from immune system

A
  • MHCI down-reg or KO

* NK killing evasion

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14
Q

Function of normal MHCI?

What binds to MHCI?

A

ALL cells present proteome antigens on MHCI

LYMPHOCYTES perform immune surverillance

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15
Q

What is the EFFECT of KO MHCI

A

No MHCI = no antigen presentation = NO CD8 cytotoxic T-cell killing

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16
Q

2 ways in which tumor cells EVADE NK cell killing?

A

Secreting INHIBITORY signals (TGFβ, PGE2) = ⬇️NK RECEPTORS

Down-reg co-stimulatory B7 = ⬇️NK ACTIVITY

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17
Q

What happens in MELANOMA with INC B7 activity?

A

INC B7 = INC NK activity = tumor free!!

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18
Q

What is B7

A

Co-stimulatory molecule for NK cells

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19
Q

3 ways in which tumor cells perform COUNTERATTACK

A
  1. CHECKPOINT inhibition
  2. APOPTOTIC escape
  3. Fas-pathway KILLING
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20
Q

How do cancer cells inhibit immune CHECKPOINTS

A

Cancer cells have PD-L1 (finger), which binds T-cell PD1 (button)
= INHIBIT T-cell signalling
= APOPTOSIS

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21
Q

How do cancer cells EVADE apoptosis?

A

Down-regualte apoptotic PROTEINS

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22
Q

In the Fas pathway, which cell DIES?

  • cell with Fas-R
  • cell with Fas-L
A

Cell with Fas-R will die

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23
Q

How do cancer cells kill T-cells via FAS pathway?

A

Fas-L (cancer cells) binds Fas-R (CTLs)

= counterattack to KILL CTLs

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24
Q

How does HIGH CD8 T-cell infiltration usually affect PROGNOSIS?

A

BETTER prognosis

25
Q

2 ways tumor cells cause T-cells DYSFUNCTION

A
  • Impair T-cell SIGNALLING

* Impair NF-kB signalling

26
Q

How do tumor cells impair T-cell SIGNALLING?

A

Tumor secretes factors to ∆signal transduction

27
Q

Is the ∆signal transduction in T-cells reversible?

Explain

A

Usually reversible if:

  • T-cell REMOVED from tumor microenvironment
  • EXCISION of tumor
28
Q

Where does impaired T-cell signalling BEGIN?

How does it progress?

A

Begins AT tumor site

Spreads to PERIPHERAL T-cells

29
Q

Why does impaired NF-kB signalling cause T-cell dysfunctin

A

NF-kB is a TF that inducdes many IMMUNE GENES

30
Q

Name 2 Tx approches to REPLACE T-cells

A
  1. Transplant cells

2. “Designer” T-cells

31
Q

In a mouse study, lymphocytes to be transplanted were cultured with WHAT factor?
Why?

A

Lymphocytes from HEALTHY mice cultured with IL-2 (induces proliferation)

32
Q

What happened when lymphocytes from HEALTHY mice were transplanted to the cancerous mouse?

A

CURED tumors in mice!

33
Q

Is this transplant method viable in HUMANS?

A

Only works in 10% of human patients…

34
Q

Name the TYPE of “designer” T-cell

A

CAR T-cells

= Chimeric Antigen Receptor

35
Q

What are the components of a CAR

A

Antibody variable region

TcR

36
Q

Benefits of a CAR lymphocyte?

A

INDEPENDENT antigen recognition = POTENT

does not require MHC or additional co-stimulation!

37
Q

2 PATHWAYS to cause immunosuppression?

A

Cellular

Soluble

38
Q

Name the 3 cellular methods of inducing immunosuppression

A

Treg
MDSCs
TAMs

39
Q

How can tumor cells use Treg cells to cause immunosuppresion?

A

Promote maturation of NAIVE Treg cells
OR
Directly stimulate MATURE Treg cells

40
Q

What are MDSCs

A

Myeloid-Derived Stem Cells

41
Q

Function of MDSCs

A

Same as Treg (also suppresses T-cell function)

42
Q

3 things secreted by MDSCs

A

O2 radicals
Arginase 1
iNOS

43
Q

What does Arginase-1 from MDSCs do?

A

Depletes L-Arginine (needed by T-cells)

44
Q

What does iNOS do?

A

Inducible NO synthase = makes NO

45
Q

What happens to the NO made by MDSCs?

A

NO combines with O2 radicals

= peroxynitrite

46
Q

How do MDSCs use peroxynitrite to kill T-cells?

A

MDSCs present antigens to T-cells

Release TOXIC peroxynitrite = KILL T-cells

47
Q

TAM infiltration = _____ prognosis

A

BAD prognosis

48
Q

What are the 2 PHENOTYPES of macrophages?

How does this CHANGE in tumors?

A 
M1 = ANTI-tumor
M2 = PRO-tumor

Tumors covnert TAMS to M2 phenotype

49
Q

Name PRO-tumor functions of M2 macrophages

A
  • Invasion (proteases)
  • Angiogenesis
  • Proliferation
  • Immunosuppression
50
Q

What factors are secreted by M2 macrophages to cause immunosuppression?

A

PD-L1
IDO1
IL10 (induces Treg cells)

51
Q

What is a SOLUBLE immunosuppression method?

A

IDO1

52
Q

Name 2 PHYSIOLOGICAL functions of IDO1

A
  • INFLAMMATION = normal immunosuppression to allow HEALING

* PREGNANCY = immune TOLERANCE of baby

53
Q

What metabolic PATHWAY is IDO1 part of?

A

KP = Kyurenine pathway

54
Q

What does INC IDO1 in cancer lead to?

A

Promote Kyurenine pathway
= 95% Tryptophan (W) depletion
= accumulation of W metabolites
= T-cell APOPTOSIS

55
Q

What is the “Double Trouble” effect caused by KP?

A

DEC Tryptophan

INC Kyurenine

56
Q

How does the “Double Trouble” effect cause immunosuppresion

DIRECTLY and INDIRECTLY

A

Directly suppress T/NK cells

Indirectly suppress T/NK cells via ⬆️Treg

57
Q

HIGH IDO1 + Kyurenine = ______ prognosis

A

POOR prognosis

58
Q

What 2 drug types used in COMBO Tx gives better outcome?

A

Checkpoint-inhibitor (anti-PD-L1)
IDO1-inhibitor

Works better as COMBO than alone

MEDSCI302 (8 decks)

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