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MFMII > Cancer Immunology > Flashcards

Cancer Immunology Flashcards

1
Q

what are the 7 key features of all cancer cells?

A
  1. they stimulate their own growth
  2. they ignore growth inhibiting signals (tumor suppressing)
  3. they avoid death by apoptosis
  4. they develop a blood supply (angiogenesis)
  5. they leave the site of origin to invade (not completely necessary)
  6. they replicate constantly to expand their numbers
  7. they evade and outrun the immune response
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2
Q

how does our body mount a response to cancer?

A

immune cells must recognize cancer cells as different from normal cells (hard bc they are our cells, but with mutations)

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3
Q

what dictates the outcome of host-tumor interactions?

A

the type of tumor Ag presented to T cells

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4
Q

what are the 2 types of tumor Ag?

A
  1. tumor specific Antigens (TSA)

2. tumor associated antigens (TAA)

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5
Q

how is TSA made?

A

mutation in tumor cell generates a new peptide that is recognized as foreign

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6
Q

why do tumors expressing TSA have better prognosis?

A

they have strong immunogenicity because they are unique Ag (altered self peptides)

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7
Q

what tumors are TSA commonly found?

A
  1. chemical and physical carcinogens

2. oncoviruses

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8
Q

what are the oncoviruses?

A 
EBV
HTLV-1
HPV
HBV
HCV
BK/JC
HHV-8
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9
Q

prognosis of tumors that express TSA

A

better prognosis, the tumors are eliminated by the body and spontaneously regress

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10
Q

how is TAA made

A

gene alteration results in overexpression of a self protein - are not mutants

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11
Q

what is needed to destroy TAA?

A

a self reactive T cell …provoke autoimmunity

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12
Q

what tumor Ag is found in the majority of tumors?

A

tumor associated antigen

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13
Q

prognosis of tumors that express TAA

A

not as good as TSA, more difficult for tumor immunity to eliminate

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14
Q

what self Ag are overexpressed in tumor cells?

A
  1. growth factors
  2. growth factor receptors
  3. oncogene coded proteins
  4. differentiation proteins
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15
Q

what is an example of a GF receptor that is a cancer?

A

Hu epidermal growth factor receptor 2 (HER2)

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16
Q

what is an example of a differentiation protein that is a cancer?

A

in melanoma, tyrosinase, gp100, melan-A and MART-1

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17
Q

what TAA are recognized as nonself?

A

overexpressed developmental Ags - oncofetal Ag

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18
Q

what are oncofetal Ag

A

Ag of embryonic development BEFORE immune system maturation

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19
Q

what is an example of an oncofetal Ag?

A
  1. Alpha fetoprotein (AFP)
  2. carcinoembryonic Ag (CEA)
  3. melanoma Ags (MAGE1-3, BAGE, GAGE1/2)
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20
Q

what oncofetal Ag is elevated in most liver cancer pt?

A

AFP (alpha fetoprotein)

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21
Q

what oncofetal Ag is elevated in 90% of colorectal cancer pt?

A

CEA (carcinoembryonic Ag)

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22
Q

why do TAA have poor prognosis?

A

they are nonimmunogenic or have weak immunogenicity

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23
Q

how are TAA useful?

A

diagnostic or prognostic markers

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24
Q

what is a good marker of tumor progression?

A

CEA – increase in serum CEA indicates tumor growth post CRC removal

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25
Q

what do serum concentrations of TAA correlate with?

A
  1. tumor size
  2. lesion differentiation
  3. response to therapy
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26
Q

how do tumors aid their growth?

A

they activate endothelia

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27
Q

how does tumor angiogenesis occur?

A
  1. tumor forms
  2. tumors that are oxygen and nutrient deficient release VEGF. pericytes that stabilized the vessel detach and the blood vessel expands
  3. activated endothelial cells produce proteases to degrade basement membrane and ECM
  4. endothelial cells begin to migrate toward the gradient of GF from the tumor
  5. endothelial cells proliferate and form new vascular structures
  6. ECM proteins are deposited as new blood vessel is stabilized by pericytes to form functional and mature blood vessel
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28
Q

how do immune cells have access to the tumor?

A

when tumor activates endothelia, they permit innate cell infiltration

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29
Q

how to macrophages respond to cancer?

A

phagocytize and present tumor Ags and kill tumor cells by ROS, NO, lysosomal enzymes and TNFalpha

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30
Q

how can Ig respond to cancer?

A

anti-Cancer Ig can bind to tumor Ags on the cancer cells to trigger ADCC – then NK come and kill
(little evidence to indicate Ig can control or eliminate)

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31
Q

how do DC respond to cancer?

A

capture tumor Ag that is released by tumor or macrophage and present to CD4 and CD8

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32
Q

how do CD4 cells respond to cancer?

A

must differentiate into IFNgamma producing Th1 cells to activate macrophages and upregulate MHC I on tumor cells

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33
Q

how does Th1 help against tumor?

A

the IL-2 produced by the Th cells drives expansion of anti-cancer CD8 T cells

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34
Q

how do NK cells respond to cancer

A
  1. activated by IL-2 or IL-12 (DC or macrophage) and express activation receptors to bind to tumor cells for release of perforin and granzyme
  2. use FcR to bind to Ig (ADCC)
  3. produce IFNgamma to activate macrophages
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35
Q

how do CD8 T cells respond to cancer

A

differentiate into CTL which are effective at eliminating cancer cells by release of perforin, granzyme, and Fas-FasL

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36
Q

?how do NK cells usually provide immunosurveillance

A

expression of MHC I on normal host cells prevents NK lysis so the inhibitory signal overrides the stimulatory signal of NK

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37
Q

how does MHC I transformation affect target/host cells?

A

transformation leads to loss of MHC I which means there is no inhibitory receptor engagement with NK, and NK lyses the cell

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38
Q

what cytokine activates NK cells

A

IL-2
IL-12
IL-15

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39
Q

what do NK cells express once they are activated?

A

activation receptors NKG2D

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40
Q

what does NKG2D do

A

is an overriding stimulatory signal induced by stress-induced ligans like MICA, MICB and others.

41
Q

how do antibodies function in tumor immunity?

A

act for opsonization and ADCC (Fc depdent phagocytosis and lysosomal degradation of tumor cell)

42
Q

why does the host response often fail to eliminate tumors?

A

tumor escape mechanisms

43
Q

how often does spontaneous regression occur?

A

1:80,000-100,000 (it’s rare)

44
Q

what drives immune evasion?

A

heterogeneity = cells at different stages of mutation means they are genetically and phenotypically unstable

45
Q

what is one feature of immunity that can promote tumor growth and survival?

A

selective pressure

46
Q

what is the consequence of specificity of immune responses?

A

selective elimination of tumor cell clones that express high levels of tumor Ag and MHC class I molecules. the immune cells get rid of all of these cells, and leaves tumor cell clones that express LOW MHC I and LOW tumor Ag that survive CTL cytotoxicity

47
Q

what is tumor editing/immunoediting?

A

selective pressure of the immune response upon the tumor population
(immune system selectively killing high MHC I and tumor Ag and leaving low MHC I and low tumor Ag)

48
Q

what is the result of tumor editing?

A

surviving tumor cell clones (Ag loss variants) now have greater resistance to host immunity and can expand to fill the void left by the destroyed cancer cells

49
Q

what do the remaining tumor cell clones express?

A

low levels of TAA and little to no TSA

50
Q

how do tumor cells evade NK cells and CTL?

A

release of soluble stress proteins

soluble MIC

51
Q

how are MIC important in tumor cell killing?

A

MIC is stress protein that is increased on tumor cells. NKG2D on NK cells bind MIC and tumor cells are destroyed

52
Q

how can tumor cells use MIC to evade killing?

A

MIC is cleaved from its cell surface and the soluble MIC binds to NKG2D on lymphocytes - they have nothing to kill because the MIC are soluble, so tumor cell survives

53
Q

how can tumor cells utilize MHC I to evade?

A

decreased synthesis or alterations of the structure of MHC class I molecules

54
Q

how do tumor cells change MHC I?

A

lack of beta-2 macroglobulin and TAP molecules prevent MHC class I expression

55
Q

if cancer cells don’t have MHC I, how do they evade killing by NK cells?

A
  1. some produce IL-10 and/or TGFbeta to suppress NK cell proliferation and function
  2. some can upgregulate HLA-E which binds NK inhibitory receptors and prevents NK cell functions
56
Q

what does HLA-E do?

A

inhibits NK by binding NK inhibitory receptors

57
Q

what does VEGF do for tumor cells other than angiogenesis

A

directly binds to DC and suppresses DC maturation, or suppresses their production in the bone marrow. therefore, tumor DC are low in number and immature.

58
Q

what is the consequence of tumors having low DC/immature DC?

A

T cells are anergic because they only have signal 1

59
Q

what is a good prognosis for tumor destruction in Treg cells?

A

Treg (CD4+ CD25+ Foxp3+) stimulate Th1 which secretes IFN-gamma to destroy tumor

60
Q

what is a bad prognosis for tumor persistence in Treg cells?

A

Treg stimulates Th2 which secretes IL-4

61
Q

how does Th17 impact tumor destruction or persistence

A

unclear – secretes IL-17 and IL-22

62
Q

what is the best mechanism for tumor destruction ?

A

Treg stimulating Th1 response for IFNgamma release

63
Q

what are tumor infiltrating T cells deviated to in the tumor?

A

Th2 and Treg cells

64
Q

what cytokines can the tumor produce?

A 
IL-10
TGFbeta 
GM-CSF
VEGF
chemokines
65
Q

what does tumor secreted IL-10 do?

A
  1. induces differentiation into Th2 which then produces IL4
  2. suppresses DC
  3. promotes TAMs
66
Q

what impact does IL-10 have on DC cells?

A

tumor DC cells have low B7, MHC II and IL-12

67
Q

what are TAMs

A

tumor associated macrophages to support macrophage activity

68
Q

what does tumor secreted TGFbeta do

A

induces Foxp3 iTreg cells to suppress inflammation

69
Q

what does tumor secreted GM-CSF do

A

acts with IL-6 and PGE2 to make monocytic precursors turn to Gr1+ CD11b+ to suppress inflammation

70
Q

what is CAF?

A

cancer associated fibroblasts

71
Q

what do CAF do

A

support cancer growth and metastasis

72
Q

what do CAF secrete?

A
  1. produce ECM and MMP for tumor spread
  2. growth factors
  3. VEGF
  4. TGF beta
  5. IL-6
  6. CXCL12 to recruit nTreg cells
73
Q

what does CXCL12 do

A

recruit natural Treg cells to high numbers

74
Q

what cells/factors regulate immunoregulation in a tumor?

A
  1. nTreg cells
  2. myeloid derived suppressor cells (MDSC)
  3. tumor associated macrophages (TAM)
75
Q

what do natural Treg cells express

A

CD4+
CD25+
Foxp3

76
Q

what do nTreg do?

A

suppress all infiltrating immune cells like DC, T cells, macrophages

77
Q

what does MDSC express

A

Gr1+

CD11b+

78
Q

what does MDSC secrete

A
  1. Arg1
  2. iNOS
  3. TGFbeta
  4. IL-10
  5. IDO
79
Q

what does Arg1 do

A

loss of arginine to block T cell activation

80
Q

what does iNOS do

A

NO reacts with TCR to reduce signaling

81
Q

what does IDO do

A

loss of tryptophan to block T cell activation

82
Q

how are TAM made?

A

monocytes exposed to IL-4, IL-13, IL-10 convert to TAM

83
Q

what do TAM secrete?

A
  1. IL-6, IL-17, IL-23
  2. Arg1 and NO
  3. PD-L1
  4. ECM
  5. VEGF
84
Q

what do IL-6, IL-17 and IL-23 do when secreted from TAM?

A

drive STAT-3 dependent tumor growth

85
Q

what do Arg-1 and NO do>

A

diminish CTL by reducing signaling and blocking activation

86
Q

what do PD-L1 do?

A

bind CTL PD-1

87
Q

why do TAM secrete ECM

A

for tumor spread

88
Q

what is the overall goal of immunoregulation in a tumor?

A

suppress responses and support tumor growth

89
Q

how is IFNalpha used as cytokine therapy to overcome tumor escape?

A
  1. induces MHC class I on tumors
  2. mature subsets of DC
  3. promote direct apoptosis of tumors
90
Q

how is IL-2 used as cytokine therapy to overcome tumor escape?

A

promotes activation/expansion of T cells and NK cells

91
Q

how is GM-CSF used as cytokine therapy to overcome tumor escape?

A
  1. mediator of hematopoiesis and monocyte-macrophage differentiation
  2. matures DC
92
Q

how is TNFalpha used as cytokine therapy to overcome tumor escape?

A
  1. induce direct apoptosis and lysis of tumors

2. mature DC

93
Q

how are immune checkpoint inhibitors used in cancer therapy?

A

tumor expresses PD-1L and B7. it binds to PD-1 and CTLA-4 on T cells and puts them in cell cycle arrest. injected Abs shut down CTLA-4 and PD-1 ligation and restore function of T cells (don’t go into cell cycle arrest)

94
Q

what is adoptive cell therapy? (ACT)

A

take own DC and T cells, culture in maturation factors like IL-2 and stimulate cells to expand. stimulate TCR without Ag! grow and transfer the cells back into the pt.

95
Q

benefit of adoptive cell therapy?

A

expands/rescues anergic tumor specific T cells and reduces numbers of Treg cells

96
Q

what are CAR?

A

chimeric antigen receptor (CAR)

97
Q

how is ACT used with CAR?

A

take CD8 T cells, remove TCR and replace with CAR. looks like T cell activation signal and has cytotoxic effects

98
Q

what do antibody-drug conjugates do?

A

target cytotoxicity to tumors usually using microtubule or mitotic inhibitors

MFMII (29 decks)

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