environmental factors that cause cancer?
carcinogens, radiation trandormation of viruses
example of benign tumor
glandular tissue. e.g adenoma
example of malignant (metastatic) tumor?
adenocarcinoma, breast cancer, prostate cancer
to a tumor to become established it needs to do what?
need to have a mechanism to evade immune mediation
indirect evidence that immune system stops most cancers
immune depleted people get more cancer
in vitro evidence
lymphoid infiltrate around tumors cerrelate with better prognosis
animal model with immune deficient.
degree of foreigness?
the amount that a molecule/antigen differ from person own molecules. for tumors, they arise from own cells, so immune system generally dont recognize self to fight it.
elimitaion phase of cance mediated by which cell?
CD4 and NK,
also gamma delta nad CD8
equilibrium phase
tumor cells acquire mutations and become resitant to CTL and NK cells
why are cancer cells so poorly immunogenic?
because they arise from one own’s self. not very foreign.
mostimpottat effectors for survailance of tumors
CD8 and CTL mediated lysis
3 mechanisms of killing by ctl and nk cells
- most efficient: perforin and granzymes (induce apoptosis in minutes)
- when Fas ligand is expressed on the surgace of CTLs and NK cells) FasL/Fas induces target cell apoptosis
- Tumor necrosis factor (TNFs) cell surface-expressed TNF-alpha (24 hours apopt.)
2 main class of antigens that recognises tumors
- Tumor specific antigens (TSA): unique cancer clone-specific Tumor antigens (ex. chemical/ radiation induced cancers)
- Tumor associated Antigens (TAA): over-expressed normal proteins, or Re-expressed normal proteins.
TSAs (tumor specific antigens)
expressed only by cancer cells, but not normal cells of that tissues, regardless of stage of differentiation. example: E6, E7 proteins of HPV virus in cervical cancer cells.
Tumor associated antigens TAAs
over-expressed normal proteins, re-expressed normal proteins
2 ways a mutation can give rise to epitope?
- mutated anchor residue of MHC?
- Mutated epitope residue?
1: mutated anchor residue of MHC: a point mutation in a self peptide allows binding of a new peptide to mhc.
2: Mutated epitope residue: a point mutation in a self peptide creates a new epitope for recognition by T cells.
number one TSA indicator?
Mutated protein . meaning that this is a protein that is produced only by the cancer cancer cell as the result of a mutation. This protein becomes an antigen and is presented to immune cells to build an immune response
tumor associated antigen think of what?
Re-expressed protein,
Over-expressed protein
PSA?
specific for protate not prostate cancer (TAA)
mechanism of tumor evasion?
- (HLA class I): downregulation of mhc1 molecule, lead to evasion of CTL cells, but becomes vulnerable to NK cells (kills cells that stops expressing MHC1).
- antigen-loss variants (evasion of antibody and CTL resposnses
- Lack of costimulatory molecules (80/86) induction of Tcell anergy
- TGF beta production: inhibition of cell mediated response and induction of regularory Tcells (Treg) in the tumor environment.
- Expression of FasL on cancer cell surface. this induces T-cell apoptosis.
- Secretion of mucopolysaccharide: will work as a physical barrier against infiltrating lymph cells and delays the expression of tumor specific antigens.
mechanism to avoid MHC1 and NK cells?
KKG2D, killing activating receptor (KAR) on some NK cells
MIC-A and MIC-B
are stress induced proteins recognized by NK cells via KAR and by gamma delta Tcells via gamma delta TCR
IFN-alpha
NK cell activation
IFN-gamma
activate CTL, up regulates HLA
IL-2
stimulates T cell and NK cell proliferation
