Parasitic infections & Tumor immunity Flashcards
Protozoa
cause chronic, non-symptomatic & latent infections
clinical manifestations in immunocompromised
cytokine milieu determines the outcome
IMMUNE EVASION: antigenic variation, different developmental (and morphological) stages
Adaptive response to protozoa
INTRACELLULAR: TH1 (activate macrophages)
EXTRACELLULAR: antibodies
cytokine milieu determines the outcome
innate response to protozoa
mentioned are only macrophages, activated via TH1
Helminths
cause chronic-persistant infections with high morbidity but low mortality
high potential for re-infections
cause immunopathology via immune-complex formation and auto-Ab
innate response to helminths
mast cells and granulocytes -> release of extracellular toxic substances
adaptive response to helminths
TH2
IgE
in late stages also TH1
Immunogenicity of tumour-Ag
- 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
Tumor-Ag presentation
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)
innate immune cells in tumours
function
detect and destroy
activate T cells (DC)
attract T cells (DC & NK cells)
Granulocytes and neutrophils
tumour
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
Arginase
causes arginin depletion -> suppresses T cell function
secreted by TAN2, TAM2, MDSC
macrophages
tumour
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
TAM1
macrophage polarization driven by TNFa
anti-tumour
- immune activation and tumour suppressive (usually for bacterial defence)
- polarization (M1) especially driven by TNFa
TAM2
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
TAN1
neutrophile polarization
TAN1: ani-tumorigenic
- immune-activating cytokines cnd chemokines
- kill tumor cells -> death receptors, ADCC, NETosis
TAN2
neutrophile polarization
TAN2: pro-tumorigenic
- cause carcinogenesis-driving inflammation (cytokines)
- suppression of T cell response -> arginase
- promotes angiogenesis and metastasis -> VEGF, MM-9
MDSC
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
MDSC
effect
EFFECT: pro-tumorigenic
- Arginase 1
- iNOS -> NO modifies TCR
- ROS -> ROS modifies TCR
- suppressive cytokines -> TGFb, IL10 induce Tregs and TAM2
MDSC subsets
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
moncytotic MDSC
PRO-TUMORIGENIC
MONOCYTOIC MDSC: Ly6C high, can differentiate into macrophages and DC
- higher suppressive capacity than grMDSC
- produce iNOS, Arginase and cytokines
granulocytotic MDSC
PRO-TUMORIGENIC
GRANULOCYTOTIC MDSC: Ly6G high
- phenotypical similar to TANs
- more abundant than mMDSC
- produce ROS and Arginase
NKT cells
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
Innate pro-tumorigenic cells
granulocytes and neutrophils (TAN2)
macrophages (TAM2)
MDSC
Innate anti-tumorigenic cells
ILC (1, 2&3 ev. not)
NKT cells
NK cells
DC
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
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
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
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
DC
migration
- MMPs degrade ECM
- active pulling along fibers of dermis
- transmigration to lymph vessels
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
DC
impairment in tumors
DC IMPAIRMENT IN TUMORS:
- reduced number and functionality
- inhibition of maturation and TME exclusion
- inhibition, metabolic stress and reduced viability
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
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
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
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
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
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
CD8 cells
killing mechanism
KILLING MECHANISMS:
- direct: perforin/granzyme, FasL mediated, Grz/GSDM
- indirect: secretion of TRAIl, FAsL, IFNg, TNFa, etc
CD8 cells
exhaustion
- prolonged Ag stimulation without clearance
- loss of effector and proliferative otential
- sustained and high expression of inhibitory moecules
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
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
IDO
degrades tryptopan -> T cell suppressive
secreted by MDSC
DCR3
decoy receptor 3
competitive inhibition by intercepting e.g. soluble death receptors/ligands
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
IFNg as therapy
cytokine therapy
IFNg: approved for leukemia and melanoma, etc
- activates CTLs and NK
- induces MHCI upregulation
- many and strong side effects
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
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
immune stimulatory antibodies
adjuvant or neo-adjuvant application
- CTLA4
- PD-1, PD-L1
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
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
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
ACT - NK cells
- isolation from blood
- expansiona and activation
- PROBLEM: short lived, many injections
prolongs leukemia survival, in solid tumors so far inefficient
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
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!
