Lecture #14

Question 1

First phase of tumorigenesis

Answer 1

Chronic inflammation (either due to infection or not)
Cells: Macrophages, mast cells, eosinophils, fibroblast, platelets, endothelial cells
Cytokines: CXCL1,2,3,5,8, VEGF, BFGF, TGFbeta, PDGF
Matrix degrading mechanisms: MMP2,9, uPA

Question 2

Second phase of tumorigenesis (by innate)

Answer 2

Elimination by the innate immunity
1. NKC reconizing MICA, ULBP1,2,3 or the lack of MHC
by NKG2D (KAR) and NKG2A (KIR)respectively
Killing by apoptosis

2. DC recognize danger signals
   Ex: extracellular DNA, RNA, urea crystals, HMGB1, HSP70,90, calreticulin.
   Recriut T cells which induce tumor cell apoptosis by FasL and further recruit M1 that cause tissue injury by ROS

Question 3

Second phase of tumorigenesis (by adaptive)

Answer 3

Tumor antigen recognition by CD8+ T cells

1. products of mutates oncogenes p53 and Ras
2. MAGEA1 overexpression
3. EBV, HPV oncogenic viral antigen
4. CEA, AFP oncofetal antigen
5. MUC1 altered surface glycoproteins and glycolipids

Question 4

APCs that phagocytosed a tumor cell or anigen present it on MHCII how can the APC activate CD8+ T cells?

Answer 4

By cross presentation of the antigen on MHCI

Question 5

What are the requirement for cross presentation?

Answer 5

1. Permission from Th1 cell by binding of CD40-CD40L
2. Danger signal for the APC
3. Support CD8+ survival by IL2 from Th1 and down regulation of PDL1 on the APC

Question 6

Third phase of tumorigenesis

Answer 6

Equilibrium

Constant production of lymphocytes

Question 7

Immunoscore method

Answer 7

Measures the amount of lymphocytes that infiltrate the cancer and surround it.
It can give us an estimation about the prognosis of the patient

Question 8

Fourth phase of tumorigenesis (5 mechanisms against the innate immunity)

Answer 8

Escape from the innate immunity
1. DC inhibition by endocytosis, down exp of MHC, down regulation of CD80/86, IDO (indolamine 2,3- dioxygenase) and arginase causing Trp and Arg deprevation for T cells

2. Antigen masking by endocytosis
3. Antigen shedding by splicing or degradation
4. Barrier formation
5. Tumor burden- clonal exhaustion

Question 9

CSC driven tumorigenesis

Answer 9

Cancer stem cells.

Small amount of CSC are able of proliferation and self renewal to produce futher tumors

Question 10

Fourth phase of tumorigenesis (mechanisms against the adaptive immunity)

Answer 10

Escape from the adaptive immunity

Inhibition of T cells
1. Locally:
- Secretion of IL10, TGF beta, VEGF, IDO
- Anergy
- Exp of FasL, TRAIL, PDL1
- Chronic inflammatory environment activates:
M2, Treg, iDC and immune complex deposition
and inhibits: Th, Tc

2. Systemically:
   Reducing CD3 zeta chain

Question 11

Adoptive cell transfer as a cancer therapy

Answer 11

Excretion of CTL - culturing in vitro - introduce tumor antigen - selection of the most tumor specific T cells - cultivation - insertion

Question 12

CAR cancer therapy

Answer 12

T cell is genetically engeneered to express anti tumor chimeric BCR

Question 13

Presentation of fetal antigens by trophoblasts is done by

Answer 13

HLA-E HLA-G which are MHCI like complexes that inhibit NKC, CTL activity
No MHCII

Question 14

Immunosuppressive mechhanisms during pregnancy

Answer 14

1. Th2 cytokine production
2. nTreg preparation of tolerogenic environment
3. iTreg enshuring tolerance, vascularization and memory
4. gamma/delta T cells secrete IL10
5. PIBE progesteron induced blocking factor:
   Inhibit NKC, AA metabolite formation
   Activate Th2 cytokine secretion