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PM3 - Infection and immunity > Parasitic infections & Tumor immunity > Flashcards

Parasitic infections & Tumor immunity Flashcards

1
Q

Protozoa

A

cause chronic, non-symptomatic & latent infections
clinical manifestations in immunocompromised
cytokine milieu determines the outcome

IMMUNE EVASION: antigenic variation, different developmental (and morphological) stages

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2
Q

Adaptive response to protozoa

A

INTRACELLULAR: TH1 (activate macrophages)

EXTRACELLULAR: antibodies

cytokine milieu determines the outcome

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3
Q

innate response to protozoa

A

mentioned are only macrophages, activated via TH1

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4
Q

Helminths

A

cause chronic-persistant infections with high morbidity but low mortality
high potential for re-infections

cause immunopathology via immune-complex formation and auto-Ab

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5
Q

innate response to helminths

A

mast cells and granulocytes -> release of extracellular toxic substances

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6
Q

adaptive response to helminths

A

TH2
IgE
in late stages also TH1

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7
Q

Immunogenicity of tumour-Ag

A
  • NEO-Ag: high, mutations give MHC binding ability or generate “new” protein
  • CANCER-TESTIS: high, hypomethylatin causes gene expression MHC-expressing tissue
  • OVEREXPRESSION: mild, overwhelm tolerance
  • TISSUE-SPECIFIC: low, no alterations, mosty used as markers
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8
Q

Tumor-Ag presentation

A

ENDOGENOUS: proteins procesed in immunoproteasome and presented on MHCI
EXOGENOUS: Ag acquisition by DCs, enhanced by immunogenic cell death (necrotic, pyroptotic cells) or exosome uptake (vesicles secreted by tumor cells)

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9
Q

innate immune cells in tumours
function

A

detect and destroy
activate T cells (DC)
attract T cells (DC & NK cells)

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10
Q

Granulocytes and neutrophils
tumour

A

in general PRO-TUMORIGENIC

TAN1: ani-tumorigenic
- immune-activating cytokines cnd chemokines
- kill tumor cells -> death receptors, ADCC, NETosis

TAN2: pro-tumorigenic
- cause carcinogenesis-driving inflammation (cytokines)
- suppression of T cell response -> arginase
- promotes angiogenesis and metastasis -> VEGF, MM-9

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11
Q

Arginase

A

causes arginin depletion -> suppresses T cell function
secreted by TAN2, TAM2, MDSC

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12
Q

macrophages
tumour

A

in general PRO-TUMORIGENIC

TAM1: anti-tumour
- immune activation and tumour suppressive (usually for bacterial defence)
- polarization (M1) especially driven by TNFa

TAM2: pro-tumour
- original for tissue repair -> promotes angiogenesis, metastasis and stemness
- polarization driven by TH2 -> IL10
- PD-L1 and CTLA4 -> inhibit T, B and NK cells
- Arginase
- immunosuppressive cytokines TGFb and IL10 -> CD4 and CD8 activity reduced
- recruit Tregs
- apoptosis of T cells via TRAL/FasL

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13
Q

TAM1

A

macrophage polarization driven by TNFa

anti-tumour
- immune activation and tumour suppressive (usually for bacterial defence)
- polarization (M1) especially driven by TNFa

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14
Q

TAM2

A

macrophage polarization, driven by IL10 (TH2)

TAM2: pro-tumour
- original for tissue repair -> promotes angiogenesis, metastasis and stemness
- polarization driven by TH2 -> IL10
- PD-L1 and CTLA4 -> inhibit T, B and NK cells
- Arginase
- immunosuppressive cytokines TGFb and IL10 -> CD4 and CD8 activity reduced
- recruit Tregs
- apoptosis of T cells via TRAL/FasL

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15
Q

TAN1

A

neutrophile polarization

TAN1: ani-tumorigenic
- immune-activating cytokines cnd chemokines
- kill tumor cells -> death receptors, ADCC, NETosis

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16
Q

TAN2

A

neutrophile polarization

TAN2: pro-tumorigenic
- cause carcinogenesis-driving inflammation (cytokines)
- suppression of T cell response -> arginase
- promotes angiogenesis and metastasis -> VEGF, MM-9

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17
Q

MDSC

A

PRO-TUMORIGENIC
myeloid derived suppressor cells
similar to TAM2 and TAN2 -> eve own subset?

EFFECT:
- Arginase 1
- iNOS -> NO modifies TCR
- ROS -> ROS modifies TCR
- suppressive cytokines -> TGFb, IL10 induce Tregs and TAM2

MONOCYTOIC MDSC: Ly6C high
- higher suppressive capacity than grMDSC
- produce iNOS, Arginase and cytokines

GRANULOCYTOTIC MDSC: Ly6G high
- phenotypical similar to TANs
- more abundant than mMDSC
- produce ROS and Arginase

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18
Q

MDSC
effect

A

EFFECT: pro-tumorigenic
- Arginase 1
- iNOS -> NO modifies TCR
- ROS -> ROS modifies TCR
- suppressive cytokines -> TGFb, IL10 induce Tregs and TAM2

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19
Q

MDSC subsets

A

PRO-TUMORIGENIC

MONOCYTOIC MDSC: Ly6C high
- higher suppressive capacity than grMDSC
- produce iNOS, Arginase and cytokines

GRANULOCYTOTIC MDSC: Ly6G high
- phenotypical similar to TANs
- more abundant than mMDSC
- produce ROS and Arginase

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20
Q

moncytotic MDSC

A

PRO-TUMORIGENIC

MONOCYTOIC MDSC: Ly6C high, can differentiate into macrophages and DC
- higher suppressive capacity than grMDSC
- produce iNOS, Arginase and cytokines

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21
Q

granulocytotic MDSC

A

PRO-TUMORIGENIC

GRANULOCYTOTIC MDSC: Ly6G high
- phenotypical similar to TANs
- more abundant than mMDSC
- produce ROS and Arginase

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22
Q

NKT cells

A

ANTI-TUMOR

innate-like cell, NK features and TCR without variability (rec. Ag presentad by CD1d)

direct killing and release of cytokines to activate immune cells

23
Q

Innate pro-tumorigenic cells

A

granulocytes and neutrophils (TAN2)
macrophages (TAM2)
MDSC

24
Q

Innate anti-tumorigenic cells

A

ILC (1, 2&3 ev. not)
NKT cells
NK cells
DC

25
Q

Innate lymphoid cells

A

ANTI-TUMORIGENIC

lineage-negative cells (T, B, myeloid, TCR)

  • ILC1: produces IFNg and TNFa -> tumour surveillance, MHCI upregulation, promotes TH1
  • ILC2: produces IL5 and IL13 -> tissue repair, helminth response, allergic inflammation
  • ILC3: produce IL7 and IL22 -> tissue repair and immune protection
26
Q

NK cells
activation, effect, tumor immune evasion mechanisms

A

ANTI-TUMORIGENIC

ACTIVATION: reduced/no MHCI, stress induced ligands (e.g. NKG2D ligands)

EFFECT:
- perforin/granzyme-mediated killing
- ADCC
- secretion of immune-stimulatory cytokines (e.g. TNFa, IFNg)
- recruitment od DC -> TME regulation

IMMUNE EVASION:
- cleavage of NKG2D ligands
- PD1-mediated NK cell suppression
- Treg, MDSC, TAM2, iDC suppress NK cells
- TME (hypoxia, pH) supress NK cells
- soluble factors impair recognition -> TGFb, HLA

27
Q

immune evasion by tumor regarding NK cells

A

IMMUNE EVASION:
- cleavage of NKG2D ligands
- PD1-mediated NK cell suppression
- Treg, MDSC, TAM2, iDC suppress NK cells
- TME (hypoxia, pH) supress NK cells
- soluble factors impair recognition -> TGFb, HLA-B

28
Q

Dendritic cells
tumor
migration, maturation & maintenance, impairment in tumors

A

ANTI-TUMORIGENIC: induction of CTL (+CD4) responses, cross-presentation of TAA and neo-Ag

in skin Langerhans cells, dermal DCs and in lymph vessels

MIGRATION:
- MMPs degrade ECM
- active pulling along fibers of dermis
- transmigration to lymph vessels

MATURATION: CLR for Ag uptake, other PRR for co-stimulator expression
- DC EDITING via NK cells: activated DCs produce cytokines activating NK cells
- reciprocal DC activation by NK cells -> SURVIVAL AND ACTIVATION

DC IMPAIRMENT IN TUMORS:
- reduced number and functionality
- inhibition of maturation and TME exclusion
- inhibition, metabolic stress and reduced viability

29
Q

DC
migration

A
  • MMPs degrade ECM
  • active pulling along fibers of dermis
  • transmigration to lymph vessels
30
Q

DC
maturation and maintenance

A

MATURATION: CLR for Ag uptake, other PRR for co-stimulator expression
- DC EDITING via NK cells: activated DCs produce cytokines activating NK cells
- reciprocal DC activation by NK cells -> SURVIVAL AND ACTIVATION

31
Q

DC
impairment in tumors

A

DC IMPAIRMENT IN TUMORS:
- reduced number and functionality
- inhibition of maturation and TME exclusion
- inhibition, metabolic stress and reduced viability

32
Q

Cancer immunity cycle

A
  • release of cancer Ag
  • presentation by DC and APC
  • priming and activation of T cells
  • trafficking to tumor
  • infiltraton
  • cancer cell recognition and killing
  • Ag release
33
Q

CD4 cells
tumor -> anti-tumorigenic subsets

A

ANTI-TUMORIGENIC

TH1: increase cell mediated immunity
- TNFa production: MHI upregulation, tumor senescence
- IFNg production: activates macrophages, MHC and Ag upregulation, tumor senescnce, reduces angiogenesis

Cytotoxic CD4: kill MHCII+ cells -> relevance questionable

Pro-tumorigenic = TH2, TH17, Treg

34
Q

CD4 cells
tumor -> pro-tumorigenic subsets

A

PRO-TUMORIGENIC

TH2: inhibit TH1 development
TH17: still unclear
Treg: tumor imunity suppression via inhibitory cytokines, trageting DC and cytotoxicity against effector T cells

35
Q

CD4 cells
importance in tumor immunity

A

providing help
DC-licensing via CD40:CD40L -> MHC upregulation, costimulators, cross-presentation and elevated CTL response
CTLs are dependen on CD4 for memory formation

36
Q

CD8 cells
tumor
killing mechanisms, cytokine production, exhaustion

A

KILLING MECHANISMS:
- direct: perforin/granzyme, FasL mediated, Grz/GSDM
- indirect: secretion of TRAIl, FAsL, IFNg, TNFa, etc

IFNg PRODUCTION: antitumorigenic, promote TH1
- stimulates ROS and NOS production by macrophages (indirect kill)
- elevated MHC expression -> more exogenous and endogenous Ag
- induces tumor senescence
- inhibits angiogenesis

EXHAUSTION: prolonged Ag stimulation without clearance
- loss of effector and proliferative otential
- sustained and high expression of inhibitory moecules

37
Q

CD8 cells
IFNg and tumor

A

IFNg PRODUCTION: antitumorigenic, promote TH1
- stimulates ROS and NOS production by macrophages (indirect kill)
- elevated MHC expression -> more exogenous and endogenous Ag
- induces tumor senescence
- inhibits angiogenesis

38
Q

CD8 cells
killing mechanism

A

KILLING MECHANISMS:
- direct: perforin/granzyme, FasL mediated, Grz/GSDM
- indirect: secretion of TRAIl, FAsL, IFNg, TNFa, etc

39
Q

CD8 cells
exhaustion

A
  • prolonged Ag stimulation without clearance
  • loss of effector and proliferative otential
  • sustained and high expression of inhibitory moecules
40
Q

intrinsic mechanisms of tumor immune evasion

A

mediated by tumor cells themselves

  • loss of Ag
  • reduced Ag presentation by loss of MHC affinity
  • inhibitory molecule expression
  • upregulation of anti-apoptotic proteins
  • downregulation of pro-apoptotic proteins
  • soluble Fas or DCR3
41
Q

extrinsic mechanisms for tumor immune evasion

A

mediated by cells other than tumor cells

  • MDSC: supress T cells via immunosuppressive molecules, IL10, TGFb, IDO
  • TAM2: secrete IL10, TGFb
  • Treg: immunosuppressive milieu -> reduces CTL function
42
Q

IDO

A

degrades tryptopan -> T cell suppressive
secreted by MDSC

43
Q

DCR3

A

decoy receptor 3
competitive inhibition by intercepting e.g. soluble death receptors/ligands

44
Q

Cytokine therapy
principle, types with side effects

A

boost of existing immunity
potential fur usage in combination (ACT) as adjuvant

IFNg: approved for leukemia and melanoma, etc
- activates CTLs and NK
- induces MHCI upregulation
- many and strong side effects

IL2 THERAPY: approved for melanoma and renal cell carcinoma
- induces proliferation and cytotoxicity of T cells
- 10% response rate and strong side effects
- combinaton would allow dose reduction

45
Q

IFNg as therapy

A

cytokine therapy

IFNg: approved for leukemia and melanoma, etc
- activates CTLs and NK
- induces MHCI upregulation
- many and strong side effects

46
Q

IL2 as therapy

A

cytokine therapy

IL2 THERAPY: approved for melanoma and renal cell carcinoma
- induces proliferation and cytotoxicity of T cells
- 10% response rate and strong side effects
- combinaton would allow dose reduction

47
Q

tumor targeting antibodies

A

opsonization for NK and macrophages
complement activation

  • Conjugation to substances (toxic and Ab-targeted delivery)
  • prevents GF binding
  • bispecific Ab (BiTE) connects target with T cell
48
Q

immune stimulatory antibodies

A

adjuvant or neo-adjuvant application

  • CTLA4
  • PD-1, PD-L1
49
Q

Vaccination with TAA

A
  • short peptides for direct MHC binding, or long for DC processing and presentation
  • TAA from tumor lysate -> can also contain self-Ag
  • requires adjuvants (TLR,RLR ligands, incomplete Freuds adjuvans)
  • monitoring
  • well tolerated but some are not immunogenic and still active immunosuppression
50
Q

Vaccination with neo-Ag

A
  • Detection is majorly problematic
  • high variability -> neo-Ag differ between patients and metastasis!
  • multiepitope vaccines or mRNA vaccines
  • stimulation with several Ag should prevent immune escape
51
Q

ACT - (CAR) T cells

A

adoptive cell transfer

  • lymphodepletion
  • specific T cells or transfection with chimeric Ag receptor
  • ex viv manipulations -> selection of specific T cells, blockage of inhibitory pathways, transgenic tumor-Ag specific TCR, chimerig Ag receptor

CAR T cells: can only recognize surface Ag

52
Q

ACT - NK cells

A
  • isolation from blood
  • expansiona and activation
  • PROBLEM: short lived, many injections

prolongs leukemia survival, in solid tumors so far inefficient

53
Q

ACT - DC

A
  • leukapharesis
  • DC, monocyte isolation
  • differentiation of monocytes to DC
  • tumor Ag loading
  • injection and adjuvans

EFFICACY: safe and tumor specific response, survival rates similar to a-CTLA4

clinical trial of loading in stu via mAB against CLRs -> no personalization required

54
Q

immunoscore

A

CTL density from 0 to 4
statistical better prognostic power than TNM model
but large heterogenicity between tumor types, patinets and samples -> time intensive!

PM3 - Infection and immunity (9 decks)

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