Week 14 - Cancer and Gestational Immunology Flashcards
What are the two edges of Tumor Homeostasis scale?
Tumor suppressor gene effects Vs. (Proto)oncogene effects
Phases of Tumors:
Tumorigenesis Elimination Equilibrium Escape (3Es)
_____ _______ is the first step of tumorigenesis!
Chronic inflammation is the first step of tumorigenesis!
macrophages, mast cells, eosinophils, fibroblasts, platelets and endothelial cells are shared cells in:
Tumorigenesis
CXCL1,2,3,5,8, VEGF, bFGF, TGFb, PDGF are shared Cytokines in:
Tumorigenesis
MMP-2, MMP-9 and uPA are all Shared matrix degrading
mechanisms for:
Tumorigenesis
Elimination - Signs of cellular stress:
ULBP1,2,3 and MICA
Elimination - signs of avoidance of adaptive immunity:
Reduction of MHC protein expression / lacking KIR (missing self recognition).
Elimination -Cells involved:
γ𝛿 T-cells and Natural Killer cells
Elimination- Danger signals recognized by dendritic cells (DCs):
What are they? (Not examples - Meaning)
These are associated with tissue injury and cell death.
Could signal of an emerging tumor.
Elimination- Danger signals recognized by dendritic cells (DCs):
Name the DC response for: Extracellular DNA and RNA
DC activation and maturation
Elimination- Danger signals recognized by dendritic cells (DCs):
Name the DC response for: Urea crystals
DC maturation
Elimination- Danger signals recognized by dendritic cells (DCs):
Name the DC response for: HMGB1 (chromatin protein)
DC Ag uptake/presentation
Elimination- Danger signals recognized by dendritic cells (DCs):
Name the DC response for: HSP70, HSP90
DC cross-presentation
Elimination- Danger signals recognized by dendritic cells (DCs):
Name the DC response for: Calreticulin
Phagocytosis by DCs
Elimination- Danger signals recognized by dendritic cells (DCs):
Name the DC response for: Phosphatidylserine, integrin
recognition by DCs (“EAT ME SIGN”)
Elimination- γ𝛿 T-cells and Natural Killer cells Mechanisms of Induction of Apoptosis: (At least 5)
- Perforin/granzyme
- TNF
- TRAIL-TRAILR1/2 contact
- IFNα/β
- IFNγ (also enhancement of the Tc/Th1 response)
Elimination- M1 cells Mechanisms of Induction of Apoptosis:
- Reactive oxygen radicals (ROI) -> tissue injury
- TNF
What are M1 cells?
Th1-polarized, tumor associated macrophage
Elimination – recognition of tumors by the adaptive
immune a system:
Products of Mutated Oncogenes and Tumor Suppressor Genes Examples
RAS
P53
Elimination – recognition of tumors by the adaptive
immune a system: Overexpressed or Aberrantly Expressed Cellular Proteins Example (Extra Knowledge)
MAGEA1
Elimination – recognition of tumors by the adaptive
immune a system: Oncogenic Virus antigens Examples
EBV
HPV
Elimination – recognition of tumors by the adaptive
immune a system: Oncofetal antigens Examples (Extra Knowledge)
CEA
AFP
Elimination – recognition of tumors by the adaptive
immune a system: Altered Cell Surface Glycolipids and Glycoproteins Example (Extra Knowledge)
MUC1
CD_+ T-cells are the main effectors of anti-tumor immunity!
CD8+ T-cells are the main effectors of anti-tumor immunity!
Tumor antigens released by the tumors can be taken up by APCs, but exogenous antigens are in the
groove of MHC II. What is the Problem with this fact?
Naive CD8+ T cells recognize antigens presented with MHC I in the lymph nodes. Therefore CD8+ T cells do not recognize them!
What is Cross-presentation? (Solving the Problem of the Other Question)
Under special conditions APCs may present exogenous antigens with MHC-I to CD8+ T cells
Requirements for Cross-presentation:
DC licensing from CD4+ Th1 cells by -
CD40 Interaction of CD4+ T cell
Requirements for Cross-presentation:
Danger signal for DCs -
TLR7 stimulation (RNA) - General Example
Requirements for Cross-presentation:
Support for CD8+ T cell survival -
IL-2 ↑
PDL1 ↓ (Programmed Death Ligand 1)
Cancers in which increased T-cell infiltration
associates with ____ prognosis.
Cancers in which increased T-cell infiltration
associates with better prognosis.
The Immunoscore is a method to estimate the ______ of cancer patients, based on the _____ cells that infiltrate cancer and surround it. It has been internationally validated in _______ cancer.
The Immunoscore is a method to estimate the prognosis of cancer patients, based on the immune cells that infiltrate cancer and surround it. It has been internationally validated in colorectal cancer.
2 methods of Antibody-mediated lysis of Tumors:
1) Complement-activation
2) ADCC
Equilibrium: Intact, organized T cell responses present
even in _______ colorectal cancer
Equilibrium: Intact, organized T cell responses present
even in advanced colorectal cancer
Equilibrium: T cell/ T Cytotox gene activity ______ correlates with chance for a relapse.
Equilibrium: T cell/ T Cytotox gene activity inversely correlates with chance for a relapse.
Escape - corruption of dendritic cells (DC) and antigen presentation: Inefficient uptake of tumor antigens - How is this Achieved?
Inhibition of DC endocytosis
Escape - corruption of dendritic cells (DC) and antigen presentation: Number of mature DC in the tumor and
draining lymph nodes↓ - How is this Achieved?
Inhibition of DC immigration / emigration
Escape - corruption of dendritic cells (DC) and antigen presentation: Antigen presentation↓ - How is this Achieved?
Inhibition of MHC I/II expression in DC
Escape - corruption of dendritic cells (DC) and antigen presentation: Tolerance against presented tumor antigens - How is this Achieved?
Down-regulation of DC costimulatory
molecules (CD80/86)
Escape - corruption of dendritic cells (DC) and antigen presentation: Trp, Arg deprivation (key metabolites for T
cells) in T cells, CD8+ T anergy and apoptosis↓, Treg
differentiation ↓, bystander DC also become tolerized ↓- How is this Achieved?
Induction of IDO (indoleamine 2,3-
dioxygenase) and Arginase expression
Escape – various other mechanisms:
Tumor cells avoid CD8+ T cell recognition - How is this Achieved?
Cessation of MHC I expression
Escape – various other mechanisms:
Antigen masking - How is this Achieved?
Immunogenic cell surface Ags disappear
from cancer cells via endocytosis
Escape – various other mechanisms:
Antigen shedding - How is this Achieved?
Alternative splicing or proteolytic degradation of the antigen allows production of a soluble form and shedding.
Escape – various other mechanisms: Barrier formation (immune privilege) - How is this Achieved?
Hard to penetrate ECM-shell or Factors are secreted from the Tumor to Produce a Shell
Escape – various other mechanisms:
Tumor burden - How is this Achieved?
Exhaustive effect on the host, IS
CSC-driven tumorigenesis (new model): Tumors are ___________ but only a ___ ________ of all tumor cells, the cancer stem cells proliferate, self-renew and form new lesions effectively.
CSC-driven tumorigenesis (new model): Tumors are heterogeneous but only a tiny fraction of all tumor cells, the cancer stem cells proliferate, self-renew and form new lesions effectively.
Cancer stem cells, like many other stem cells are, compared to the majority of tumor cells -they are: (2)
A) less immunogenic
B) more resistant to immune-mediated lysis
M1 macrophages (Th1-polarized), NK, NKT, γ𝛿 T, CD8+ T cells, CD4+T cells, mDC-k (mature DCs) - are all examples for cells that Promote Tumor ______ and Part of the _____ Inflammation process.
M1 macrophages (Th1-polarized), NK, NKT, γ𝛿 T, CD8+ T cells, CD4+T cells, mDC-k (mature DCs). These are all examples for cells that Promote Tumor Rejection and Part of the Acute Inflammation process.
M2 macrophages (Th2-polarized), MDSC-k (Myeloid-Derived Suppressor Cell:CD11b+ /GR1+ myeloid cells) Mast cells, D25+ Foxp3+ Treg, iDC-k (immature DCs), Immune complex deposition - are all examples for cells that Promote Tumor ______ and Part of the _____ Inflammation process.
M2 macrophages (Th2-polarized), MDSC-k (Myeloid-Derived Suppressor Cell:CD11b+ /GR1+ myeloid cells) Mast cells, CD8+ T cells, CD4+ T cells, D25+, Foxp3+. Treg, iDC-k (immature DCs), Immune complex deposition - are all examples for cells that Promote Tumor Escape and Part of the Chronic/Abnormal Inflammation process.
What are the cytokines Tumor secrete in order to promote escape?
immunosuppressive cytokines :IDO, IL-10, TGFβ and VEGF
Escape: Local Effects -T cell anergy with recruitment of abnormal inflammatory cells ___: Ag presentation without _________.
Escape -T cell anergy with recruitment of abnormal inflammatory cells iDC (immature DC): Ag presentation without costimulation.
Escape: Local Effects - NOS
NO Synthesis and Arginase Production
Escape: Local Effects - reduction of the T cell lifespan by the tumor:
TRAIL or PDL1 expression
FasL are a Hypothesis
Escape: Systemic effects -
interference with _ cell signaling
Escape: Systemic effects -
interference with T cell signaling
Escape: Systemic effects -
reduced ____ ____ chain expression
Escape: Systemic effects -
reduced CD3+ zeta chain expression
Escape: Systemic effects -
inhibition of ____ activation
Escape: Systemic effects -
inhibition of NF-kB activation
Escape: Systemic effects -
interference with the ____ signaling
Escape: Systemic effects -
interference with the STAT signaling
Escape – Immunoediting - Definition
Unsuccessful attempts to eliminate cancer over a long time, sooner or later inevitably select out tumor cells that are resistant to most antitumor immune mechanisms (the tumor is ”edited” by the IS).
Rituximab, Ibritumomab, Tositumomab, Alemtuzumab, Gemtuzumab…etc - These are:
FDA-approved immunotherapies - Monoclonal antibodies
BCG, Imiquimod - These are:
FDA-approved immunotherapies - Adjuvants
What are the Cytokines given as a FDA-approved immunotherapies ?
IFNa, IL-2, TNFa
What are examples of Supportive therapies given as a FDA-approved immunotherapies ?
G(M)-CSF (Myelosuppressive)
Leucovorin (MTX Rescue)
FDA-approved immunotherapies - Prophylaxis for:
HPV vaccine and HBV vaccine :
Antibiotics:
NSAID (FAP, ulc. colitis):
FDA-approved immunotherapies - Prophylaxis for:
HPV vaccine and HBV vaccine : Oncogenic Viruses
Antibiotics: Removal of Oncogenic Bacteria (H.Pylori)
NSAID (FAP, ulc. colitis): Inhibition of Chronic Inflam.
Bone marrow transplantation - 2 options
Allogeneic and DLI
Blockade of tumor receptors promoting growth Induction of apoptosis via receptors,
Complement mediated lysis of tumor cells, ADCC against tumor cells, Carrying a prodrug, a toxin, or a radioactive isotope to tumor cells. These are all examples for _________ _____-based immunotherapies.
Blockade of tumor receptors promoting growth Induction of apoptosis via receptors,
Complement mediated lysis of tumor cells, ADCC against tumor cells, Carrying a prodrug, a toxin, or a radioactive isotope to tumor cells. These are all examples for Monoclonal antibody-based immunotherapies.
Example: Treatment of Basal cell carcinoma with Imiquimod /Aldara (TLR7 agonist) - This is an example of ______-based tumor immunotherapies. This causes a conversion of the Chronic ____ controlled Inflammation to an Acute one.
Example: Treatment of Basal cell carcinoma with Imiquimod /Aldara (TLR7 agonist) - This is an example of Adjuvant-based tumor immunotherapies. This causes a conversion of the Chronic Tumor controlled Inflammation to an Acute one.
Tumor antigen-based immunotherapies: active specific immunization - could be achieved by a ____ of allogeneic tumor cells mixed with PAMPs
Tumor antigen-based immunotherapies: active specific immunization - could be achieved by a lysate of allogeneic tumor cells mixed with PAMPs
Tumor antigen-based immunotherapies: active specific immunization - ______ tumor antigens
mixed with PAMPs
Tumor antigen-based immunotherapies: active specific immunization - conserved tumor antigens
mixed with PAMPs
Tumor antigen-based immunotherapies: active specific immunization - tumor cells that were genetically modified to express _____________ cytokines (add and Example).
Tumor antigen-based immunotherapies: active specific immunization - tumor cells that were genetically modified to express immunostimulatory cytokines (e.g. GM-CSF to support DC maturation).
Tumor antigen-based immunotherapies - Stopping spontaneous or tumor-induced T-cell suppression:
CTLA-4 blockade (In T Cells), How is it helpful?
Eliminates Tumor Inhibition of DC-T cells co-stimulation and Tumor recognition
What causes expression of PDL1 on Tumor cells? (2)
1) Constitutive Oncogenic Signaling
2) T-cell Induction
Tumor antigen-based immunotherapies - Stopping spontaneous or tumor-induced T-cell suppression:
- PD-1 blockade (In T Cells), How is it helpful?
Eliminates Tumor Negative regulation CD8+T cells.
Tumor antigen-based immunotherapies - Stopping spontaneous or tumor-induced T-cell suppression:
- PDL1 blockade (In Tumors), How is it helpful?
Eliminates Tumor Negative regulation CD8+T cells.
In contrast to targeted therapies, _____ _______ ______ induces long term responses, but only in a fraction of all patients.
In contrast to targeted therapies, Immune checkpoint blockade induces long term responses, but only in a fraction of all patients.
Cancers with ____ rate of genomic ______ are the
most responsive to ICB (e.g. _______)
Cancers with high rate of genomic mutations are the
most responsive to ICB (e.g. melanoma)
Current antitumor immunotherapies - virotherapies:
Oncovirus is an ________ virus that invades both Healthy cells and _____ cells.
Current antitumor immunotherapies - virotherapies:
Oncovirus is an attenuated virus that invades both Healthy cells and Tumor cells.
Current antitumor immunotherapies - virotherapies:
Oncovirus ______ in the tumor cell and causes eventual _____ releasing: TSAs and _______ and causing acute inflammation and _______ of tumor.
Current antitumor immunotherapies - virotherapies:
Oncovirus replicates in the tumor cell and causes eventual lysis releasing: TSAs and GM-CSF and causing acute inflammation and rejection of tumor.
Current antitumor immunotherapies - virotherapies:
Oncovirus is an ________ virus that is doesn’t ______ in healthy cells.
Current antitumor immunotherapies - virotherapies:
Oncovirus is an attenuated virus that is doesn’t replicate in healthy cells.
Current antitumor immunotherapies - Adoptive cell transfer (ACT): Tumor fragments cultured in ____, Induction of tumor infiltrating ____ T cell (TIL) proliferation with ___ and finally Re-introduction of tumor-specific ____ T cells that have been massively cultured.
Current antitumor immunotherapies - Adoptive cell transfer (ACT): Tumor fragments cultured in vitro, Induction of tumor infiltrating CD8+ T cell (TIL) proliferation with IL-2 and finally Re-introduction of tumor-specific CD8+ T cells that have been massively cultured.
CAR therapy - What is the meaning of the name?
T cells receive tumor-specific CHIMERIC BCR-ANTIGEN RECEPTOR (CAR therapy) via gene editing.
CAR therapy example - T cells with anti-CD19
BCR to treat CD19+ B-___.
CAR therapy example - T cells with anti-CD19
BCR to treat CD19+ B-ALL.
CAR therapy 1st generation: scFv anti-CD19- BCR fusioned with ____ to provide TCR-like signals by the BCR.
CAR therapy 1st generation: scFv anti-CD19- BCR fusioned with CD3ε to provide TCR-like signals by the BCR.
CAR therapy 2nd generation: scFv anti-CD19- BCR fusioned with CD3e and ____/______ domains to provide co-stimulation too.
CAR therapy 2nd generation: scFv anti-CD19- BCR fusioned with CD3e and CD28/4-1BBL domains to provide co-stimulation too.
CAR therapy 3rd generation: scFv anti-CD19-BCR fusioned with CD3e and ____ independent costimulatory _______.
CAR therapy 3rd generation: scFv anti-CD19-BCR fusioned with CD3e and multiple independent costimulatory domains.
scFv: What is it ? What does it contain?
CAR therapy
Single-chain variable fragment. Containing genetically engineered VH and VL subdomains for BCR function in modified CAR T cells.
CAR therapy can be combined with:
Immune checkpoint blockade.
Elimination Early classification: ____-______ ______ (TSA), which are present exclusively on tumor cells (rare) and _____-________ _______ (TAA), which are present both on tumor and normal normal cells.
Elimination Early classification: Tumor-Specific Antigens (TSA), which are present exclusively on tumor cells (rare) and Tumor-Associated Antigens (TAA), which are present both on tumor and normal normal cells.
The fetus is a ____-allograft.
The fetus is a hemi-allograft.
The fetus as hemiallograft - Name the Immunological Viewpoint Matching the Physiological one : Insemination
Transplantation
The fetus as hemiallograft - Name the Immunological Viewpoint Matching the Physiological one :Pregnancy
Tolerance
The fetus as hemiallograft - Name the Immunological Viewpoint Matching the Physiological one : Abortus
Acute rejection
The fetus as hemiallograft - Name the Immunological Viewpoint Matching the Physiological one :Birth
Timely rejection
Recognition of fetal antigens by the mother - Antibodies against paternal antigens in __% of primiparae, in __-__% in multiparae .
Recognition of fetal antigens by the mother - Antibodies against paternal antigens in 20% of primiparae, in 40-60 % in multiparae.
Presentation of fetal antigens:
• No ______ on trophoblast cells
• Monomorphic _____-like molecules:
_____, _____: Inhibition of CD8+ T cells and NK cells
Presentation of fetal antigens:
• No MHC-II on trophoblast cells
• Monomorphic MHC I-like molecules:
HLA-G, HLA-E: Inhibition of CD8+ T cells and NK cells
Immunosuppression in pregnancy: associated cells
γ𝛿 T-cells and T-Reg cells
Which Cytokines are used by γ𝛿 T-cells and T-Reg cells in Immunosuppression in pregnancy?
TGF-β, Th2 cytokines
Which Endocrine factors released by fetus are contributing to Immunosuppression in pregnancy?
Endocrine - Fetal:
• α-1-fetoprotein
Which Endocrine factors released by mother are contributing to Immunosuppression in pregnancy?
Endocrine - Maternal:
• Progesterone, estrogen
• Placental (chorion)
• hCG
What is PIBF?
Progesterone induced blocking factor
Effects of PIBF
- __ cells are inhibited
- Th-2 cytokine _____
- anti-_____ effects
- inhibits ________ metabolism
- Asymmetric antibodies _____
Effects of PIBF
- NK cells are inhibited
- Th-2 cytokine excess
- anti-abortive effects
- inhibits arachidonic metabolism
- Asymmetric antibodies elevated
