Tumor Immunology

Question 1

Summary of mutation acquisition in colorectal cancer:

Answer 1

• Tumor suppressor gene (APC) lost –> epithelial proliferation
• Oncogene (RAS) activated –> small benign tumor
• Tumor suppressor gene (CDD) lost –> large tumor
• Tumor suppressor gene (p53) lost –> invasive tumor
• Rapid accumulation of mutations –> metastasis

Question 2

Carcinoma

Answer 2

Epithelial cell tumor

Question 3

Leukemia

Answer 3

Tumor of circulating cells

Question 4

Lymphoma

Answer 4

Solid tumors in lymph nodes

Question 5

Myeloma

Answer 5

Tumors of bone marrow cells

Question 6

Sarcoma

Answer 6

Tumors of connective tissue cells

Question 7

How do some viral proteins cause unchecked proliferation of human cells?

Answer 7

Blocking p53 and Rb (tumor suppressor genes)

Question 8

Cancer-causing viruses:

Answer 8

HPV, Hep B, EBV, HTLV-1, HIV-1 and HHV8

Question 9

Tumor cells can’t grow in a different person. Why not?

Answer 9

Differences in MHC haplotypes - rejection of tumor cells

Question 10

Tumor-specific antigen?

Tumor-associated antigen?

Answer 10

• Changes in genome lead to expression of antigens not in healthy cells (NEW antigens)
• Antigens that are LESS expressed in healthy cells
• REACTIVATION of embryonic genes not seen anymore
• OVEREXPRESSION of self-protein

sorry for all the yelling ^

Question 11

What cells look for tumor antigens?

Answer 11

CD4, CD8, B cells

Question 12

What do NK cells do to tumor cells?

Answer 12

Kill them, if they are MHC-1-negative or coated with antibody

Question 13

Some examples of over-expressed or aberrantly expressed antigens in tumor cells?

Answer 13

Tyrosinase, MAGE, gp100, MART

Question 14

What are some oncogene / tumor suppressor products?

Answer 14

Oncogene: mutated Ras, Bcr/Abl fusion proteins

Tumor suppressor: mutated p53 protein

Question 15

What are MAGE-1 and MAGE-3?

Answer 15

Embryonic antigens (normal testicular protein) expressed in melanoma, breast cancer, glioma

Question 16

What is MUC-1?

Answer 16

Abnormal post-translation modification antigen expressed in breast and pancreatic cancers

Question 17

What is tyrosinase?

Answer 17

Enzyme in pathway of melanin synthesis expressed in melanomas

Question 18

What does it mean when HPV type 16, E6 and E7 proteins are expressed?

Answer 18

Oncoviral; cervical carcinoma

Question 19

What cancer is MART2 seen in?
ME1?
p53?
KIAA0205?
Triosephosphate isomerase?

Answer 19

• Melanoma
• Lung carcinoma
• Head/neck squamous-cell carcinoma
• Bladder tumor
• Melanoma

Question 20

What cancer is BCR-ABL fusion protein seen in?

Answer 20

Chronic myelogenous leukemia

Question 21

How do these cells kill tumor cells?
CD4
CD8
NK
gd T cells
Eosinophils
B cells

Answer 21

CD4: cytokines to control other immune cells
CD8: direct lysis
NK: direct lysis
gd T cells: cytokines and lysis
Eosinophils: degranulation
B cells: Ab to tumor cells (facilitate NK lysis or activate complement)

Question 22

Complexes of ________ are taken up by DCs and presented to CD4 and CD8

Answer 22

tumor antigens and heat-shock proteins

Membrane fusion allows presentation of tumor Ag to CD8

Question 23

How tumors evade the immune response:

Answer 23

• Out-growth of antigen-negative variants (lose antigen; can’t be recognized)
• Loss / reduction of MHC expression (lack of T cell recognition)
• Secretion of immunosuppressive cytokines (TGF-beta and Th2 cytokines)
• Induce CTL apoptosis
• Lack of co-stimulatory signals
• Soluble tumor antigens (tolerance)
• Shedding of MHC class I-related chain (MIC) - ligand of NKG2D (activates NK cell) - avoid NK cells

Question 24

What do tumor cell secrete to inhibit T cells from killing them?

Answer 24

TGF-beta (inhibit T cells, induce Treg)

Treg –> TGF-beta, IL-10 (inhibit T cells)

Question 25

How can the BCG vaccine (for TB) help treat bladder cancer?

Answer 25

Adjuvants activate APCs and other cell via TLRs; increase the T cell response

Question 26

Immunotherapies against tumor cells:

Answer 26

• Antibody against tumor antigen (like anti-CD20)
• Tumor vaccines: tumor taken at surgery, manipulated –> express B7, GM-CSF, IL-12 (also can use tumor antigens, HSP, telomerase, CEA)
• DC therapy: isolated from patients, loaded with tumor antigen, injected to boost T cells
• T cell therapy: patient’s T cells activated in vitro with tumor antigens and cytokines (IL-12), injected back in

Question 27

What is Sipuleucel-T?

Answer 27

Cancer vaccine for prostate cancer

Fusion protein of antigen prostatic acid phosphatase (PAP) and GM-CSF –> induce DCs in vitro that will present antigen on MHC II –> back in patient

Question 28

Describe some monoclonal antibodies for cancer therapy.
Rituxan
Herceptin (Trastuzumab IgG1)
Erbitux
Avastin

Answer 28

Rituxan: Anti-CD20 targets B cells (non-Hodgkins lymphoma)
Herceptin: Anti-EFG-receptor-2 (HER2) - breast cancer
Erbitux: Anti-EGFR (HER1) - metastatic colorectal cancer
Avastin: Block VEGF receptor (anti-angiogenesis)

Question 29

Describe some monoclonal antibodies for cancer therapy.
Zevalin
Bexxar

Answer 29

Zevalin: Radiolabeled anti-CD20 for B cell lymphoma
Bexxar: Radiolabeled anti-CD20 (very similar)

Question 30

Radiolabeled antibodies for cancer detection:

Answer 30

OncoScint (colorectal and ovarian - use TAG 72)

ProstaScint (prostate - PAP)

Question 31

How does Brentuximab-vedotin IgG1 work?

Answer 31

IgG antibody (anti-CD30) conjugated to auristatin with a cathepsin-cleavable linker
- Internalized; auristatin enters nucleus and binds microtubules - cell can't divide and dies

Question 32

What does anti-CTLA4 do?

Answer 32

Block CTLA4 from inhibiting T cell activation (CTLA4 preferentially bind the co-activator B7 - normally binds CD28 on the T cells)

ex: ipilimumab (melanoma pts.)

Question 33

Chimeric antigen receptor (CAR) on T cells helps target them to even tumor cells that they’re not specific for. What do they target on the cells?

Answer 33

CD19

Components of CAR: Ig chain (VL and VH), CD28, CD137, chain of CD3