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PathoPhys > Lecture 5 - Tumor immunology > Flashcards

Lecture 5 - Tumor immunology Flashcards

1
Q

explain the concept of ‘immune surveillance of cancer’?

A

a physiologic function of the immune system is to recognize and destroy clones/ trasformed cells before they form tumors, and kill tumors once they’re formed

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2
Q

t/f: both adaptive and innate immune systems fight against tumor formation, which has been proven by both animal and human studies

A

true

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3
Q

do tumors possess antigens?

A

yes - this is how they can be recognised as non-self

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4
Q

t/f: immune responses frequently fail to prevent tumor growth

A

true

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5
Q

why is the immune surveillance of cancer a field of interest in medical science? Why not just focus on treatment types?

A

because it is a potential treatment type - the immune system can be activated by external stimuli to kill tumor cells

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6
Q

Can tumors stimulate immune responses - considering they have formed from the hosts own cells?

A

Yes

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7
Q

How can immune cell presence and tumors be linked, in terms of prognosis of disease?

A

If a tumor is surrounded by many mononuclear cells (lymphocytes, NK cells, macrophages - involved in adaptive response) it implies a more positive prognosis (they might fuck that thing upppp!)

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8
Q

define immunoscore?

A

The Immunoscore is a method to estimate the prognosis of cancer patients, based on the immune cells that infiltrate cancer and surround it - higher immunoscore, lower clinical impact :)

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9
Q

State the principal means by which the adaptive immune system kills tumor cells?

A

CD8+ cells (cytotoxic T cells)

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10
Q

CD8+ cells are likely to kill which…

a. ) Cells overexpressing MHC II
b. ) Cells not expressing MHC II
c. ) Cells expressing MHC I
d. ) Cells not expressing MHC I

A

c

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11
Q

t/f: CD8+ cells do not perform any type of surveillance function

A

false - they do, looking for who has MHC I to kill

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12
Q

what’re CD8+ cells which are found inside tumors called? What’s their function?

A

Tumor-infiltrating lymphocytes; have capacity to kill tumor cells

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13
Q

Tumor specific CD8+ cells are often difficult to detect within patients. Why may this be?

A

due to regulatory mechanisms undergone by tumor cells - they prevent specific CD8+ formation by inhibitory pathways

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14
Q

Tumor cells undergo inhibitory pathways to prevent the formation of CD8+ cells which would specifically target them. How can this problem be solved? (simple answer)

A

the inhibition of these inhibitory pathways by the tumor (disinhibition), this leads to large CD8+ cell response!

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15
Q

NK cells kill (many/ few) types of tumor cells

A

many; variable

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16
Q

NK cells kill tumor cells which exhibit what?

A
  • reduced MHC class I

- ligands for NK cell activation

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17
Q

state the 3 possible outcomes of natural immunosurveillence applied to a premalignant lesion (tumor)?

A
  1. Tumor escapes, metastases
  2. Equilibirum, tumor remains same size
  3. Elimination, tumor destroyed
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18
Q

what is another name for CD8+ cells?

A

CTL - cytotoxic lymphocyte

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19
Q

what does the immunoscore consider?

A
  1. immune cell type (CTL’s & memory cells good)
  2. immune cell quantity (more the better)
  3. density (denser the better)
  4. location (inside tumor and outside better)
  5. immune functional orientation (what functions the cells have)
  6. immune gene signatures
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20
Q

the immunoscore considers immune functional orientation. What is the desired functional orientation for fighting off tumors?

A
  • TH1 cells to stimulate cellular response
  • cytotoxic factors (granzymes, IFN-Y, IL-12/15)
  • chemokines to attract adaptive immune cells
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21
Q

explain the relationship between CTL’s (CD8+ cells), NK cells and MHC class I?

A 
CTL's kill cells which express MHC class I 
NK cells kill cells which do not possess MHC class I

(cells = pathogenic only, obvs not all cells)

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22
Q

which cell is the “bridge between innate and adaptive immunity”?

(he said it like 5 times in this lecture so its gotta be worth sumn)

A

NK cells

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23
Q

t/f: NK cells do not kill virally infected cells

A

false

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24
Q

why do NK cells only kill cells not expressing MHC class I?

A

Because MHC class I sends inhibitory signals to NK cells

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25
Q

Why do NK cells kill cells without MHC I, whereas CTL’s kill cells with it? What’s the point?

A

It’s to have a more well rounded immune response: tumor cells try to survive against tumor-infilitrating-lymphocytes (TIL, CD8+ cells) by not expressing MHC class I (because thats what the CD8+ cells are looking for). However, they are subsequently killed by NK cells, which have developed to kill pathogenic cells not expressing MHC class I, essentially “rounding up the survivors”

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26
Q

Asides from lack of MHC class I, how else may tumor cells activate NK cells/ NK cells be activated to kill tumors? (4)

A
  1. LIGANDS - tumors express MIC-A, MIC-B, ULB. These are ligands used to activate NKG2D receptor on NK cells, activating them
  2. IMMUNOGLOBINS - IgG coated tumor cells become target of NK cells as they have Fc receptors to recognize them
  3. CYTOKINES - (IFN-Y, IL-15/12) activate NK cells and increase tumoricidal capacity
  4. LAK - Lymphokine-activated killer (LAK) cells are activated by IL-2
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27
Q

MIC-A, MIC-B, ULB are AKA?

A

“stress proteins” exhibited by tumors

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28
Q

Do macrophages inhibit or promote cancer growth?

A

Either - depends on their activation state. Typically, M1 macrophages kill tumors like brazyy

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29
Q

how are macrophages activated by tumors?

A

Not 100% known, maybe:

  1. recognizing damage associated molecular patterns from dying tumor cells
  2. activation of macrophages by IFN-y (which is produced by tumor specific T cells)
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30
Q

how do macrophages kill tumor cells?

A

same mechanisms used to kill infectious organisms, ie. use of NO

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31
Q

how may macrophages promote tumor growth?

A

M2 phenotype of macrophage:

  • secrete VEGF
  • secrete TGF-B
  • secrete soluble factors promoting tumor angiogenesis
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32
Q

Name some tumor antigens (4, get atleast 3)

A

Cyclin dependent kinase 4
B-Catenin
Caspase-8
MAGE-1/3

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33
Q

MHC is found on ___ ___ ___, which gets an ____ from tumor cells and presents it to ____ ___ ___

A

APC’s; antigen; inactive T cells

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34
Q

define antigenecity

A

the capability of an antigen to bind to receptors on immune cells (T cells, B cells)

mauro seems to also think it means the amount of antigens on tumor, ie. more antigens = higher antigenecity

so mutation in DNA -> neoantigen formation -> immune response, reflected as a high antigenecity

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35
Q

if a tumor has high antigenecity, what is the likely outcome in terms of tumor growth?

A

reduced/ slowed, antigen is recognised as non-self an immune system attacks

36
Q

define neoantigen

A

antigen newly formed due to mutation; the peptide brought about due to mutation

37
Q

tumors with defect in ____ ___ ____ have more neo-antigens than other tumors

A

DNA repair machinery

more different DNA -> more different proteins (antigens) -> mount larger immune response

38
Q

a tumor involving low somatic mutation prevalence is likely to have (many/ few) antigens, thus the possibility it is recognised by the immune system is (high/ low)

A

few; low

39
Q

what’re the 2 major types of antigens associated w tumors?

A

tumor specific

tumor associated

40
Q

define epitope

A

part of antigen antibody binds to

41
Q

define HLA

A

human leukocyte antigens - protein markers on most cells of the body, used to recognise as self

42
Q

describe some factors determining antitumor T cell reactivity?

A
  1. MODULATED HLA - Ability of T cell to recognize epitope is modulated by host HLA type
  2. INTRATUMORAL HETEROGENETIY - allows individual tumor cells to escape recognition
  3. HEIRARCHIES - T cell immunodominance heirarchies make some Ag bigger targets
  4. LACK RECEPTOR - Holes in T-cell receptor repertoire and T cell tolerization and exhaustion can limit response efficacy
43
Q

cancer cell activity leads to unfavourable conditions in tissue microenvironment (due to altered metabolism). State these (4)

A
  1. relative hypoxia
  2. altered nutrient availability
  3. presence immunosuppressive signals
  4. waste accumulation
44
Q

____ derived cells inhibit the immune response vs cancer

A

myeloid

45
Q

t/f: myeloid cells (MDSC)use both immune and non-immune mechanisms to promote tumor progression

A

true

46
Q

MDSC AKA

A

myeloid cells

47
Q

what immune mechanisms do MDSC’s use to promote tumor progression

A
  1. inhibit adaptive immunity - suppress CD4+ and CD8+ activity and function, drive and recruit Treg cells
  2. inhibit innate immunity - polarize macrophages (promoting them into M2 phenotype, inhibit NK cytotoxicity
48
Q

what do Treg cells do?

A

T- regulatory cells suppress the immune response

49
Q

what non-immune mechanisms do MDSC’s use to promote tumor progression?

A
  • promote cancer cell stemness
  • facilitate angiogenesis
  • drive tumor invasion & metastasis
50
Q

t/f: MDSC’s only have negative effects on the body

A

false

51
Q

what does MDSC stand for?

A

myeloid derived suppressor cell

52
Q

state some beneficial effects of MDSC’s

A
  • lower blood glucose
  • reduction insulin tolerance
  • increase maternal-foetal tolerance and embryo implantation
53
Q

How may tumors evade an immune response being triggered? (2)

A
  1. Lack of T cell recognition of tumor:
    a. ) mutation in MHC genes (tumor cell) needed for antigen processing by T cell
    b. ) failure to produce tumor antigen
  2. T cell inhibition:
    b. ) secretion of immunosuppressive proteins inhibiting T cell
    c. ) expression inhibitory cell surface proteins inhibiting T cell activation
54
Q

other then specific mechanisms employed by tumor cells to evade immune response, why else may the immune system struggle to react to these potentially deadly threats?

A

Tumor cells are derived from host cells and so resemble normal cells, thus many are lowly immunogenic

55
Q

define immunogenic

A

able to mount an immune response

56
Q

Many tumors are weakly immunogenic.

a. ) Which tumors are strongly immunogenic?
b. ) Which tumors are especially weakly immunogenic?

A

a. ) those induced by oncogenic viruses (viral proteins are foreign antigens)
b. ) Spontaneous tumors

57
Q

Why are spontaneous tumors weakly immunogenic, as oppose to those induced by oncogenic viruses?

A

Because spontaneous tumors grow in the tissue giving them time to develop mutations for undetectability

58
Q

Give the 3 general reasons as to how tumors evade an immune response?

A
  1. Tumor mechanisms
  2. Tumor resemblance
  3. Tumor rapid growth (overwhelms I.S., not all malignant cells can be destroyed)
59
Q

t/f: it is not possible for the immune system to eliminate ALL tumor cells, completely destroying the tumor

A

False - it is haha idiot

60
Q

Tumor cells take advantage of inhibitory pathways of the immune system.

a. ) What inhibitory pathways specifically?
b. ) Why do these inhibitory pathways exist in the immune system in the first place?

A

a. ) CTLA-4, PD-1

b. ) As the immune system needs to regulate itself - prevention of hypersensitivities

61
Q

what is CTLA-4?

A

a receptor which downregulates the immune response when activated

62
Q

what is PD-1?

A

“programmed cell death protein-1”

a receptor which downregulates the immune response when activated (suppresses T cell)

63
Q

what is PD-L1?

A
  • a ligand binding to PD-1 receptor
  • B7 family protein
  • expressed on many tumors
64
Q

a. ) Where is PD-1 found?

b. ) Where is PD-L1 found?

A

a. ) T cells, a receptor
b. ) tumor cells & possibly APC’s, a ligand

(remember - the L stands for ligand!)

65
Q

Secreted products from tumor cells may suppress the immune response. Provide an example of this?

A
  • TGF-B secreted in large quantities
  • inhibits proliferation and effector functions of lymphocytes and macrophages

PD-L1 also

66
Q

What are Treg cells?

A

T-regulator cells, suppress immune system

67
Q

How are Treg cells involved in tumors impacts?

A

patients with tumors express
a.) higher then usual Treg cells, and
b.) Treg cells within cellular infiltrates in tumors
meaning immune cell is suppressed more

68
Q

Which phenotype of macrophages support tumors?

A

M2 phenotype

69
Q

how do M2 macrophages support tumors?

A

mediator secretion -

  1. IL-10, prostaglandin E2 both impair T cell activation and effector function
  2. TGF-B, VEGF both promote angiogenesis about tumor
70
Q

t/f: M1 macrophages may also support tumor growth

A

false - only M2

M1=good, M2=bad

71
Q

Mechanisms of tumor immunotherapy?

A
  1. Cytotoxic T cell targeting (bispecific antibodies)
  2. Tumor cell vaccine
  3. Host dendritic cell (DC) vaccination (DC acts as an APC)
  4. Alloreactivity
  5. transfer of tumor reactive cells
72
Q

Explain some recent advancements in the field of treating tumors via inhibition of inhibitory pathways?

A
  1. Anti-PD-1/ anti-PD-L1 antibodies used to treat advanced tumors, blocking the PD-1 on tumor specific T cells
  2. Anti-CTLA-4 antibodies used to treat melanomas, likely blocking the CTLA-4 on effector T cells and Treg cells
73
Q

explain the fundamental principal of adoptive cell therapy?

A
  1. lymphocytes (blood, tumor infiltrate) isolated
  2. expanded in culture with IL-2, may be transfected with CAR gene
  3. infused back into patient in supplement with extra IL-2
74
Q

what are CAR genes? What are they composed of?

A

Genes for “recombinant Chimeric Antigen Receptors” on T cells

They are composed of receptor domains specific for tumor antigens & signaling domains (ie. ITAMS, these promote robust T cell activation)

75
Q

what is the main complication with adoptive cell therapy?

A

high cost

76
Q

APC’s contain a wide variety of molecular ‘checkpoints’, which are essentially different signaling molecules. Do these activate, or inhibit T cells?

A

Could be either - depends on the molecule and receptor. The point of this question is to emphasize APC’s can either activate, or inhibit T cells, depending on the circumstance

inhibiting could be PD-L1 released onto PD-1 receptor

activating could be CD40 onto CD40L

77
Q

what ligand binds to:

a. ) CTLA4
b. ) PDL1 (this can be receptor somehow)
c. ) PD1

A

a. ) CD80, CD86
b. ) CD80
c. ) PDL1, PDL2

these all cause inhibition T cell
(this is all that Mauro said to know for this big slide)

78
Q

activated T cell makes ___ which increases PD-L1 expression, in effort to regulate immune system

A

IFN-Y

79
Q

state a type of anti-CTLA4 antibody?

A

ipillimumab, or Nivolamb

80
Q

state a type of anti-PDL1 antibody?

A

Pembrolizumab

81
Q

Can ipillimumab and Pembrolizumab be used together?

A

Yes, but better to use sequentially

82
Q

The first therapy based on gene transfer involved CAR genes. State the drug used, and general purpose?

A

Kymriah used to introduce CAR genes into T cells of a patient, augmenting the patients own cells to fight off leukemia. This is done through the process of adoptive cell therapy (discussed earlier).

83
Q

State the substance Tumors use to degrade the extra-cellular matrix?

A

Matrix metallo-proteinases (MMP)

84
Q

When would MMP be used?

A

MMP used by tumor breaking off from initial site, to degrade ECM and allow for intravasation

85
Q

What’re the 4 most common destinations for tumor metastasis?

A

lung, liver, lymph nodes, bone

86
Q

how do tumors promote inflammation?

A

tumor cells have lots of an enzyme called CO22, COX2 produces prostalgandin-E2, which promotes inflammation

(note: PgE2 also inactivates T cells)

PathoPhys (25 decks)

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