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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
Innate lymphoid cells
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
NK cells activation, effect, tumor immune evasion mechanisms
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
immune evasion by tumor regarding NK cells
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
Dendritic cells tumor migration, maturation & maintenance, impairment in tumors
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
DC migration
- MMPs degrade ECM - active pulling along fibers of dermis - transmigration to lymph vessels
30
DC maturation and maintenance
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
DC impairment in tumors
DC IMPAIRMENT IN TUMORS: - reduced number and functionality - inhibition of maturation and TME exclusion - inhibition, metabolic stress and reduced viability
32
Cancer immunity cycle
- 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
CD4 cells tumor -> anti-tumorigenic subsets
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
CD4 cells tumor -> pro-tumorigenic subsets
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
CD4 cells importance in tumor immunity
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
CD8 cells tumor killing mechanisms, cytokine production, exhaustion
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
CD8 cells IFNg and tumor
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
CD8 cells killing mechanism
KILLING MECHANISMS: - direct: perforin/granzyme, FasL mediated, Grz/GSDM - indirect: secretion of TRAIl, FAsL, IFNg, TNFa, etc
39
CD8 cells exhaustion
- prolonged Ag stimulation without clearance - loss of effector and proliferative otential - sustained and high expression of inhibitory moecules
40
intrinsic mechanisms of tumor immune evasion
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
extrinsic mechanisms for tumor immune evasion
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
IDO
degrades tryptopan -> T cell suppressive secreted by MDSC
43
DCR3
decoy receptor 3 competitive inhibition by intercepting e.g. soluble death receptors/ligands
44
Cytokine therapy principle, types with side effects
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
IFNg as therapy
cytokine therapy IFNg: approved for leukemia and melanoma, etc - activates CTLs and NK - induces MHCI upregulation - many and strong side effects
46
IL2 as therapy
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
tumor targeting antibodies
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
immune stimulatory antibodies
adjuvant or neo-adjuvant application - CTLA4 - PD-1, PD-L1
49
Vaccination with TAA
- 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
Vaccination with neo-Ag
- 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
ACT - (CAR) T cells
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
ACT - NK cells
- isolation from blood - expansiona and activation - PROBLEM: short lived, many injections prolongs leukemia survival, in solid tumors so far inefficient
53
ACT - DC
- 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
immunoscore
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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