Tumor Immunology Flashcards
Summary of mutation acquisition in colorectal cancer:
- 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
Carcinoma
Epithelial cell tumor
Leukemia
Tumor of circulating cells
Lymphoma
Solid tumors in lymph nodes
Myeloma
Tumors of bone marrow cells
Sarcoma
Tumors of connective tissue cells
How do some viral proteins cause unchecked proliferation of human cells?
Blocking p53 and Rb (tumor suppressor genes)
Cancer-causing viruses:
HPV, Hep B, EBV, HTLV-1, HIV-1 and HHV8
Tumor cells can’t grow in a different person. Why not?
Differences in MHC haplotypes - rejection of tumor cells
Tumor-specific antigen?
Tumor-associated antigen?
- 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 ^
What cells look for tumor antigens?
CD4, CD8, B cells
What do NK cells do to tumor cells?
Kill them, if they are MHC-1-negative or coated with antibody
Some examples of over-expressed or aberrantly expressed antigens in tumor cells?
Tyrosinase, MAGE, gp100, MART
What are some oncogene / tumor suppressor products?
Oncogene: mutated Ras, Bcr/Abl fusion proteins
Tumor suppressor: mutated p53 protein
What are MAGE-1 and MAGE-3?
Embryonic antigens (normal testicular protein) expressed in melanoma, breast cancer, glioma
What is MUC-1?
Abnormal post-translation modification antigen expressed in breast and pancreatic cancers
What is tyrosinase?
Enzyme in pathway of melanin synthesis expressed in melanomas
What does it mean when HPV type 16, E6 and E7 proteins are expressed?
Oncoviral; cervical carcinoma
What cancer is MART2 seen in? ME1? p53? KIAA0205? Triosephosphate isomerase?
- Melanoma
- Lung carcinoma
- Head/neck squamous-cell carcinoma
- Bladder tumor
- Melanoma
What cancer is BCR-ABL fusion protein seen in?
Chronic myelogenous leukemia
How do these cells kill tumor cells? CD4 CD8 NK gd T cells Eosinophils B cells
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)
Complexes of ________ are taken up by DCs and presented to CD4 and CD8
tumor antigens and heat-shock proteins
Membrane fusion allows presentation of tumor Ag to CD8
How tumors evade the immune response:
- 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
What do tumor cell secrete to inhibit T cells from killing them?
TGF-beta (inhibit T cells, induce Treg)
Treg –> TGF-beta, IL-10 (inhibit T cells)
How can the BCG vaccine (for TB) help treat bladder cancer?
Adjuvants activate APCs and other cell via TLRs; increase the T cell response
Immunotherapies against tumor cells:
- 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
What is Sipuleucel-T?
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
Describe some monoclonal antibodies for cancer therapy. Rituxan Herceptin (Trastuzumab IgG1) Erbitux Avastin
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)
Describe some monoclonal antibodies for cancer therapy.
Zevalin
Bexxar
Zevalin: Radiolabeled anti-CD20 for B cell lymphoma
Bexxar: Radiolabeled anti-CD20 (very similar)
Radiolabeled antibodies for cancer detection:
OncoScint (colorectal and ovarian - use TAG 72)
ProstaScint (prostate - PAP)
How does Brentuximab-vedotin IgG1 work?
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
What does anti-CTLA4 do?
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.)
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?
CD19
Components of CAR: Ig chain (VL and VH), CD28, CD137, chain of CD3
