Tumor immunology

Question 1

Overview of immune surveillance

Answer 1

Immune system recognizes + removes tumors

• adaptive -> viral proteins, mutations, abnormally expressed self-antigens
• measurable T cell and antibody response to cancers
• immunosuppression -> cancer (esp viral)

Question 2

Immune editing

Answer 2

New/accurate term for immune surveillance

Elimination - NK, T infiltrate tumor -> eliminate or fail ->
Equilibrium - dormant, kept in check by CD8, NK
Escape - mutations to evade response -> clinical disease

Question 3

Tumor antigens

Answer 3

Necessary for CD8 and antibody responses!

Tumor specific (TSA) - unique, recognized as foreign
- ex mutated protein, viral
Tumor associated (TAA) - also found on normal cells (mis- or over-expression)
- ex oncofetal antigens, self-antigens

Question 4

Viral tumor antigens

Answer 4

Viruses -> 60% of all cancers
Strongly antigenic (foreign protein)

Ex: EBV, HTLV (human T-lymphotropic), HPV, hep B and C

Good vaccine target
More common in immunosuppressed

Question 5

Mutated tumor antigens

Answer 5

Can often be recognized by immune system

Unique peptide -> new anchor residue or new TCR residue
- different from self so no central or peripheral tolerance to these lymphocytes

Often individual although there are some clusters if same carcinogen (ex BRCA)

Question 6

Oncofetal antigens

Answer 6

Found on all cells during development (embryo or fetal) -> re-expressed

• ex carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP)
• tumor “associated”

Diagnostic use via monoclonal antibodies to antigen

• monitor CEA in serum -> tumor burden, tx effect
• enzymes -> immunohistology or whole body imaging

Question 7

Self-antigens in tumors

Answer 7

No immune response unless tolerance mechanisms overcome!

Melanoma = same antigens as melanocytes
- immune response -> autoimmunity -> vitiligo

Can mark stage of differentiation

• CD marker on leukemia, lymphoma -> cell lineage and stage
• (B cell and T cell tumors actually express tumor specific antigen in Ig or TCR)

Question 8

Tumor immune evasion

Answer 8

How do tumors escape immune surveillance?

• tolerance (TAA vs TSA), make T cells unresponsive
• selection for non-antigenic cells
• immunosuppression (release TGF-b, IL-10)
• low immunogenicity (low MHC class I -> avoid CD8 -> NK response but less acute and no memory)
• induce Treg and suppressor cells

Question 9

Overview of tumor immunotherapy

Answer 9

Either antigen specific (T or B cells -> antigens) or non-specific (total activation)
Either active (host response) or passive (administer effector cells or molecules)

Ex:

• immunostimulants (active, nonspecific)
• antibodies to TSA (passive, specific)
• tumor vaccines (active, specific)
• adoptive T cell therapy (passive, specific)

Question 10

Nonspecific biological response modifiers

Answer 10

Non-specific, active - immunostimulants
BCG, C. parvum -> strong immune response
 - produce cytokines, activate macrophages
 - cytokines alone don't work
IFN-a, IL-12 -> melanoma

Question 11

Antibodies to tumor antigens

Answer 11

Specific, passive -> complement -> ADCC, phago, apoptosis
- can also couple to toxin or radiation
Difficult to get exact match!
Requires functioning immune system

Examples of tumor specific antigens
- idiotype region of B or T cell tumor (monoclonal)
- mutant EGF-receptor with missing extracellular domain
Effective therapies:
- herceptin = anti-HER2/neu (breast CA)
- Rituxan = antiCD20 for B cell tumors

Question 12

Immune-stimulatory antibodies

Answer 12

Non-specific active therapy
Use monoclonal Ab as immunostimulants

Ipilimumab - anti-CTLA4 - blocks T cell inhibition

-> leads to autoimmunity as side effect

Question 13

Tumor vaccines

Answer 13

Specific, active therapy
Prophylactic for associated virus (ex HPV)
Existing cancer - only effective if minimal/residual disease
- whole tumor cells - alter to make GM-CSF, attenuate
- purified antigen or peptide + adjuvant
- DNA -> transfect APCs -> cross-priming -> CD8
- Activate dendritic cells -> inject into nodes

Question 14

Adoptive T-cell therapy

Answer 14

Specific, passive therapy

Tumor infiltrating lymphocytes (both CD8, CD4)

• > remove, expand, activate (cytokines) -> reinfuse
• can be TSA-specific idiotype
• can be polyclonal -> engineer specific TCR -> reinfuse
• often deplete lymphocytes first to provide “space” for graft
• usu maintain response with vaccines, cytokines