Tumor Immunology

Front 1

Cancer
Define and does the immune see cancer cells as 'foreign.'

Back 1

A diverse collection of diseases that result from abnormal and invasive cell proliferation
Not efficiently

Front 2

Cancer arises through mutations of __________ cell DNA

Back 2

Somatic

Front 3

Tumor

Back 3

Tissue in which cells are multiplying abnormally

Front 4

Metastasis

Back 4

Spreading of tumor cells through the lymph or blood

Front 5

Carcinomas

Back 5

Cancers of epithelial cells

Front 6

Sarcomas

Back 6

Cancers of other cells

Front 7

Cancers of the immune system:
Leukemis
Lymphomas
Myelomas

Back 7

Involving circulating cells
Involving solid lymphoid tumors
Involving bone marrow

Front 8

What can initiate cancer? What are they called?
What are mutagenic agents that increase mutation rates?

Back 8

Exposure to chemicals, radiation, and viruses (mutagens)
Carcinogens

Front 9

True or false. Some tumors express tumor specific antigens that can be recognized by the immune system.

What kills the tumor cell?

Back 9

True
CD8 effector T cell response (CTLs)

Front 10

What is a tumor specific antigen?
Describe the mechanism of presentation.

Back 10

Antigen expressed only by tumor cells.
Cancer arises and mutates the normal cellular proteins. The normal determinants are lost and new ones are created. Becomes a source of peptides for proteosome degradation and presentation on MHC Class I molecules. Determinants were not available during T cell development and negative selection in thymus, so CD8 T cells may have specificity for new "mutant" determinant.

Front 11

Can tumors arise when embryonic genes are reactivated?
How does the immune system respond?
What is this an example of?

Back 11

Yes
Embryonic proteins reactivated and loaded onto MHC Class I for presentation to naive T cells. (again, thy were not available during negative selection).
Tumor-associated antigen

Front 12

What is a tumor-associated antigen?

Back 12

Un-mutated protein that is encoded on the germ-line DNA of a cell whose expression level has been dramatically altered by a neoplastic event/process.

Front 13

Can mutations from tumor formation result in increased expression of a normal self protein by the tumor cells?
What is this another example of?

Back 13

Yes
Tumor associated antigens
Increase in normal self determinants can also lead to recognition by effector CTLs

Front 14

Describe the mouse experiment.

Back 14

Tumor cells injected into identical MHC (syngeneic) mouse = tumor grows, mouse dies
Tumor cells injected in to different MHC (allogenic) mouse = tumor is "rejected," mouse lives

CTLs recognize allogenic peptides derived from mismatched MHC class I expression

Front 15

True or false. Most people are tolerant against peptides derived from the mutant forms of tumor suppressor genes or oncogenes.

Back 15

FALSE! Most people are NOT TOLERIZED against them.

Front 16

What happens (in general) when tumor cells divide and proliferate?
How is the immune system involved?

Back 16

Multiple mutations occur even in genes that have nothing to do with cell division regulation.
Any mutation can create unique host determinants that can be recognized by some of the CD8 T cells

Front 17

What is an example of a normal cellular protein that is abnormally expressed in a tumor cell that can serve as a tumor antigen?

Back 17

MAGE, GAGE, BAGE, and RAGE proteins (vaccine potential)
MAGE = expressed in testes only normally (immunoprivileged site), upregulated and serves as a target for CTLs

Front 18

What is an example of an unmutated oncogene over-expressed on tumor cells?

Back 18

HER2/NEU = over expression used as targets for treatment with monoclonal antibody drugs

Front 19

What are oncofetal antigens?

Back 19

Genes only expressed during embyronic development that are de-repressed in some tumors
--> can also serve as CTL targets

Front 20

Most tumors express elevated levels and/or abnormal forms of surface ________________ and _________________.
How can these be used?
What are some examples?

Back 20

Glycoproteins and glycolipids
Diagnostic markers/therapy targets
Gangliosides, blood group antigens, and mucins.

Front 21

What are some mucins of interest?

Back 21

CA-125 and CA-19-9 (ovarian carcinomas)
MUC-1 in many breast carcinomas has epitopes that can be recognized by CTLs and antibodies
POSSIBLE MUC-1 VACCINE?

Front 22

What are cell specific differentiation antigens?
Does the host make immune responses against them?
Can they serve as therapeutic targets?

Back 22

Antigens normally expressed by cells at different levels of differentiation.
Whatever type was there at the time of the neoplastic event remains there.
No, the host is tolerant to them.

Front 23

Can tumor antigens be produced by oncogenic viruses?
Examples?
Can they be recognized by the immune system?

Back 23

Yes
HPV and EBV
Yes

Front 24

What is the general mechanism for how tumor cells can evade immune responses?
What are more specific mechanisms?

Back 24

Antigenic drift = as tumor grows, mutations occur
1/3-1/2 of all tumors have defects in MHC Class I (evade CTL, but more of a target for NK)
Produce TGF-beta to downregulate immune response
Expression of Fas-ligand on surface (apoptose CTLs)
Expression of PD-L1 ligand for protein PD-1 which causes downregulation of T cell effector function.

Front 25

Three ways to use humanized monoclonal antibodies:

Back 25

Ligand agonists or antagonists
Conjugated to toxins or radionuclides (targeted killing of tumor cells)
Target for killing by NK cells (ADCC) and via complement cascade (CDCC) (MAC)

Front 26

What are some examples of antagonist action of Mabs?

Back 26

IL-6 receptor blockage
VEGF (binding to ligand to prevent it from binding to receptor) = toxin or pathogen neutralization
Depletion of receptors by endocytosis

Front 27

What is agonist action by Mabs?

Back 27

Bind to receptor and mimic signaling
Promote signaling through receptor by recruiting ligand

Front 28

What are some effectors of cell killing by Mabs?

Back 28

Recruit host immune responses (NK cells, ADCC, etc.)
Activation of complement cascade (high copy numbers of antibodies bound directly to host cells)
Conjugation to toxins, radionuclides, or drugs.

Front 29

Why is T-DM1 a unique product?

Back 29

Combines a Mab drug with a chemotherapy drug, making it good for pre-treated HER2-positive breast cancers.

Front 30

What is PD-1?
Are tumors that express PD-L1 protected from CTL-mediated killing?
How do we overcome this?

Back 30

A member of the CD28/CTLA-4 family expressed on the surface of effector T cells.
Normally ligands are expressed on APCs in secondary lymphoid tissue (to keep control of CTLS in this area)
YES!
Need a Mab specific for either receptor or ligand to block interaction.

Front 31

What is a promising combination therapy?

Back 31

anti-CTLA-4 and anti-PD-1 (for melanoma)

anti-CTLA-4 = prevents activation of TREGS which would secrete TGF-B and down regulate T cells
anti-PD-1 = prevents the PD-L1 from binding to PD-1 on CTLs and downregulating their effector function.

Front 32

What are bispecific Mabs?

Back 32

One arm specific for CD3 and one arm specific for tumor
Hmmmm...basically pulls the two together.

Front 33

What is CAR (chimeric antigen receptor)?

Back 33

Creation of chimeric CD8 T cells with specificity determined by antibody specificity (instead of T cell receptor specificity).
Generate monoclonal antibodies for a tumor determinant
Heavy and light chain coding regions used to encode a single chain chimeric chain that includes CD3 zeta-chain. (recognition through B cell immunoglob chain and signaling through CD3 receptor)
T cell receptors do not normally recognize cell surface glycolipids or glycoproteins (so this is a better technique).