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Pathophysiology 2.0 > Week 6 lec - tumours > Flashcards

Week 6 lec - tumours Flashcards

1
Q

The concept of immune surveillance of cancer, which was proposed by Macfarlane Burnet in the 1950s, states that?

A

a physiologic function of the immune system is to recognize and destroy clones of transformed cells before they grow into tumors and to kill tumors after they are formed

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2
Q

what are the three possible outcomes of premalignant lesions?

A

escape - the immune system cannot fight it and it becomes a primary tumour and metastasises

equilibrium - the immune system can control the growth of the lesion but can’t remove it

elimination - immune system destroys premalignant cells

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3
Q

how does the immune system recognise tumours?

A

the express certain Ags

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4
Q

this picture seems really important, make some flashcards based on it when you actually understand what’s going on

A
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5
Q

what are the 3 key concepts in tumour immunity?

A
  1. tumours express Ags which the host immune system recognises as foreign
  2. immune response often fails to prevent tumour growth
  3. the immune system can be activated by external input to eradicate tumours
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6
Q

what is the mononuclear cell infiltrate that many tumours are surrounded by composed of?

A

T lymphocytes, natural killer (NK) cells, and macrophages

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7
Q

what types of cells are present in lymph nodes draining the sites of tumour growth?

A

activated lymphocytes and macrophages

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8
Q

does the presence of lymphocytic infiltrates in some types of melanoma and carcinomas of the colon and breast predict a better or worse prognosis?

A

better

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9
Q

immunoscore measures the density of what T lymphocyte populations in the core or periphery of tumours?

A

CD3, CD8 and CD45RO

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10
Q

what has a better prognosis, an immunoscore of 0 or of 4?

A

4

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11
Q

what chemokines in a tumour site are associated with survival?

A

CX3CL1, CXCL9, CXCL10, CCL5 and CCl2

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12
Q

what cytotoxic factors in a tumour site are associated with survival?

A

the usual lads - granzymes, perforin and granulysin

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13
Q

what Th1 cell-associated factors in a tumour site are associated with survival?

A

IFNy, IL-12, T-bet and IRF1

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14
Q

what effect would you expect finding Th17, Treg and Th2 cells in a tumour site to have on survival?

A

variable effect depending on tumour type

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15
Q

what effect would TLS have on survival?

A

the presence and quality has a positive association with survival

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16
Q

what is the principal mechanism of adaptive immune protection against tumors?

A

killing of tumor cells by CD8 + CTLs

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17
Q

how do CTLs recognise tumours?

A

by tumour Ag peptides which are presented on MHC1 molecules

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18
Q

prognosis which particular type of tumour is more favorable when more CTLs are present within the tumor?

A

colonic carcinomas

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19
Q

what does TIL stand for?

A

tumour-infiltrating lymphocyte

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20
Q

TILs extracted from human solid tumours contain CTLs with the capacity to do what?

A

kill the tumour from which they were extracted

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21
Q

a recent clinical trial has demonstrated that ? can lead to the development of strong T cell responses against the tumor?

A

blocking these inhibitory pathways, and thus removing the brakes on immune responses

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22
Q

NK cells kill many types of tumour cells, especially those that have what?

A

reduced class I MHC expression and express ligands for NK cell–activating receptors

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23
Q

In vitro, can NK cells kill virally infected cells?

A

yes

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24
Q

In vitro, what type of tumour is especially vulnerable to NK cells?

A

hematopoietic tumors

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25
Q

what do NK cells respond to tumours with an absence of MHC1?

A

because MHC1 produce inhibitory signals to NK cells

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26
Q

Some tumors also express MIC-A, MIC-B, and ULB.

What are they?

A

ligands for the NKG2D activating receptor on NK cells

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27
Q

Fc receptors (FcγRIII or CD16) on IgG antibody–coated tumor cells can do what?

A

target NK cells to them

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28
Q

what effect does cytokines interferon-γ (IFN-γ), IL-15, and IL-12 have on NK cells?

A

increases NK tumoricidal capacity

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29
Q

what are IL-2–activated NK cells called?

A

lymphokine-activated killer (LAK) cells

30
Q

what are lymphokine-activated killer (LAK) cells derived by?

A

culture of peripheral blood cells or tumor-infiltrating lymphocytes from tumor patients with high doses of IL-2

31
Q

which are more potent killers of tumors, unactivated NK cells or lymphokine-activated killer (LAK) cells?

A

lymphokine-activated killer (LAK) cells (IL-2–activated NK cells)

32
Q

what do activated M1 macrophages do?

A

kill many tumor cells

33
Q

Macrophages are capable of both inhibiting and promoting the growth and spread of cancers, depending on what?

A

their activation state

34
Q

how are macrophages activated by tumours?

A

it is not yet known, probably by recognition of dying tumour cells or IFNy produced by tumour specific T cells

35
Q

what is the main mechanism that M1 macrophages use to kill tumour cells?

A

production of nitric oxide (NO) (the same mechanisms that they use to kill infectious organism)

36
Q

what type of macrophages are believed to contribute to tumour progression?

A

those with an M2 phenotype

37
Q

how do M2 phenotype macrophages contribute to tumour progression?

A

secrete vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and other soluble factors that promote tumor angiogenesis.

38
Q

what types of tumour antigen does melanoma express? (3)

A
  1. cyclin-dependent kinase 4, a cell-cycle regulator
  2. B-Catenin, a relay in signal transduction pathway
  3. MAGE-1/MAGE-3, normal testicular proteins
39
Q

what type of tumour antigen does squamous cell carcinoma express?

A

caspase-8, a regulator of apoptosis

40
Q

give 2 classes of potential tumour rejection antigens?

A
  1. tumour specific mutated oncogene or tumour suppressor
  2. germ cell

(these are the ones from the lecture but there are heaps more, page 721 in janeways has heaps)

41
Q

what type of tumour antigens does melanoma, breast, and glioma tumours express

A

MAGE-1/MAGE-3, normal testicular proteins

42
Q

how many peptides do tumour antigens usually have?

A

8-10, give or take

43
Q

what are the 5 steps of tumour Ag immune response?

A
44
Q

what would you rather have, high or low tumour antigenicity?

A

high

45
Q

what type of mutation causes a neoantigen and consequently an immune response?

A

non-synonymous mutation

46
Q

what type of tumours have more neo- antigens than others tumors

A

Tumors with defect in the DNA repair machinery

47
Q

which type of cancer has the most neoantigens?

A

melanoma

48
Q

what are the top found neoantigen producing tumours?

A
  1. melanoma
  2. lung squamous
  3. lung adeno
  4. stomach
  5. eosophagus
49
Q

this…

was a fucking slide…

in the lecture…

WTF?

(you should probably check this study out, chances are mauro will put a question in the test on it)

A
50
Q

which two major types of Ags can be recognized by endogenous T cell responses?

A

tumor-associated and tumor-specific Ags

51
Q

what is an epitope?

A

the part of an antigen molecule to which an antibody attaches itself

52
Q

what is the ability for epitopes derived from these Ags to be detected by responding T cells modulated by?

A

the host’s HLA type and the epitope’ processing and presentation efficiency

53
Q

what can intratumoral heterogeneity lead to?

A

individual tumor cells to escaping recognition

54
Q

how can ntratumoral heterogeneity allow individual tumor cells to escape recognition?

A

On the T cell side, immunodominance hierarchies can be generated leading to an individual Ag being the major target of the response.

55
Q

what effect can holes in the TCR repertoire and T cell tolerization and exhaustion have on response efficacy?

A

it can limit it

56
Q

what does cancer cell activity leads to within the TME (tumour microenvironment)?

A
  1. altered nutrient availability
  2. presence of immunosuppressive signals
  3. relative hypoxia
  4. waste accumulation
57
Q

here’s an awesome picture showing how tumours can reduce T cell activity, make some flashcards on it

A
58
Q

what do myeloid-derived supressor cells do?

A

halt immune response vs cancer

59
Q

drawbacks of myeloid derived suppressor cells?

A
  1. inhibit adaptive antitumor immunity: suppressing CD4 and CD8 T cell activation and function, and by driving and recruiting T regulatory cells
  2. inhibit innate immunity: polarizing macrophages toward a type 2 tumor-promoting phenotype and by inhibiting NK-mediated cytotoxicity.
  3. growth/proliferation: promote cancer cell stemness, facilitate angiogenesis, and drive tumor invasion and metastasis
60
Q

benefits of MDSC?

A
  1. lowering of blood glucose levels and reduction of insulin tolerance in obese individuals
  2. maintenance of maternal- fetal tolerance and embryo implantation during pregnancy
61
Q

3 main ways tumour evade the immune system?

A
  1. failure to produce Ag = lack of T cells recognition
  2. MHC1 mutation = lack of T cells recognition
  3. secretion of immunosuppressive proteins or expression of inhibitory cell surface proteins = inhibition of T cell activation
62
Q

what type of tumors that elicit strong immune responses?

A

those induced by oncogenic viruses, in which the viral proteins are foreign antigens

63
Q

what type of tumors induce weak or even undetectable immunity?

A

Many spontaneous tumours derived from host cells

64
Q

why does the importance of immune surveillance and tumor immunity varies with the type of tumor?

A

because many spontaneous tumours appear similar to host cells to the immune system, whereas virus-induced tumours may present foreign Ags therefore be more immunogenic

65
Q

what are the main reasons that anti-tumor immunity is unable to eradicate transformed cells?

A
  1. many tumors have specialized mechanisms for evading host immune responses.
  2. tumor cells are derived from host cells and resemble normal cells in many respects. Therefore, many tumors tend to be weakly immunogenic. Many spontaneous tumors induce weak or even undetectable immunity. This may be because the tumors that grow have undergone mutations that reduce their ability to stimulate strong immune responses.
  3. the rapid growth and spread of a tumor may overwhelm the capacity of the immune system to effectively control the tumor, which requires that all the malignant cells be eliminated.
66
Q

what are the two best-defined inhibitory pathways in T cells?

A

CTLA-4 or PD-1

67
Q

how is T cell response inhibited to some tumors?

A

CTLA-4 or PD-1 involvement

68
Q

what is a possible reason that CTLA-4 is involved in tumour immunosuppression?

A

When tumor antigens are presented by APCs in the absence of strong innate immunity and thus with low levels of B7 co-stimulators. These low levels may be enough to engage the high-affinity receptor CTLA-4.

69
Q

what is PD-L1?

A

a B7 family protein that is a ligand for the T cell inhibitory receptor PD-1

70
Q

how is PD-1 involved in tumour immunosuppression?

A

PD-L1, a B7 family protein that is a ligand for the T cell inhibitory receptor PD-1 is expressed on many human tumors, and animal studies indicate that anti-tumor T cell responses are compromised by PD-L1 expression.

PD-L1 on APCs may also be involved in inhibiting the activation of tumor-specific T cells.

71
Q

blockade of what 2 pathways is now being used in the clinic to enhance tumour immunity?

A

CTLA-4 and PD-L1/PD-1

72
Q
A

Pathophysiology 2.0 (19 decks)

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