Transcript Tumor antigens

TUMOR-IMMUNITÄT
A.K. Abbas, A.H. Lichtman, S. Pillai (6th edition, 2007)
Cellular and Molecular Immunology
Saunders Elsevier
Chapter 17, immunity to tumors
„Immune surveillance“ hypothesis
(Macfarlane Burnet, 1950s)
importance still controversial
but:
it is clear that immune system reacts against tumor cells
one of the factors in growth of malignant tumors:
ability to evade or overcome mechanisms of host defense
increased incidence of some tumor types in immunocompromized
experimental animals and humans
immune mechanisms can be exploited to destroy tumors
Expermental evidence:
Methylcholantrene(MCA)
-induced tumors
Tumor antigens:
Tumor-specific: TSA
Oncogenic mutants of normal cellular genes:ras, bcr-abl, p53
Randomly mutated genes: TSTA´s (tumor-specific transplantation antigens)
Can be identified: biochemical
cDNA cloning
Tumor-associated: TAA
Normal cellular proteins aberrantly expressed
Tyrosinase - melanomas (enzyme melanin biosynthesis)
Cancer/testis antigens: expressed testis and trophopblasts
Oncofetal antigens: developing fetal tissue
CEA: carcinoembryonic antigen - colo and many cancers,
AFP: -fetoptotein - hepatocellular cancer and others
not specific, can be induced inflammatory conditions
Altered glycolipid and glycoprotein antigens:
gangliosides - in melanomas
Mucin-1 - O-linked carbohydrates
Tissue-specific differentiation antigens
Antigens of oncogenic viruses:
DNA-viruses:
EBV: Epstein-Barr
HPV: papilloma
Animals:
Papovaviruses: SC40, polyoma
Adenoviruses
RNA viruses:
Animal models
In humans only HTLV-1 known: ATL, infects CD4+ cells
Tumor antigens recognized by T cells
Immune responses to tumors
Innate:
NK: MHC low, ligands for activating receptors (MICA, B, ULBP)
LAK cells (IL2)
Macrophages: direct by receptors ?
IFN- from T lymphocytes
Adaptive:
CD8+ cells:
Clear for carcinogen-induced and virus-induced tumors
Less clear for spontaneous
But: tumor-specific CTL can be isolated from tumors
Cross-presentation by professional APCs necessary
To differentiate CD8+ cells to antitumor CTLs
Use of pulsed DCs in tumor therapy
CD4+ cells: not so clear
Cytokines for CTL development
TNF and IFN- - macrophage activation
Antibodies: complement, Fc receptor (macrophages, NK)
Little evidence for in vivo effective humoral response
Evasion of immune responses:
Induction of tolerance:
MMTV
SV40T transgenic
Anergy induction by presentation by APC inducing tolerance
Regulatory T cells: found in tumors
Loss of antigen expression
MHC downregulation
Failure to induce CTL: no costimulators or MHCII
Products suppressing immune response:
TGF-
Fas-L
masking of cell surface: sialic acid containing mucopolysaccharides
Immunotherapies
Stimulation of active immune response
Vaccination:
Killed tumor vaccines + adjuvants
Purified tumor antigens
Pulsed DCs
Cytokines and co-stimulator enhanced vaccines
DANN vaccines
Viral vectors: tumor antigens + cytokines
Preventive versus therapeutic:
hepatitis B
HPV
Augmentation by costimulators: B7
and cytokines: Il2, IL4, IFNs, GMCSF, TNF, IL12
Blocking inhibitory pathways: CTLA4 (autoimmunity !)
Bacillus Calmette-Guerin
Anti-CD3
Passive immunotherapies:
LAK: from PBLs, IL2
In mice impressive effects
In patients wide individual variation
TILs: from inflammatory infiltrate
Graft versus leukemia effect
Anti-tumor antibodies - humanized
Anti-CD30
Anti-HER2
Couped to toxins: ricin, diphteria toxin
Radioisotopes
Anti-tumor drugs
Anti-EGF: colorectal cancer
Anti-VEGF: in combination with chemotherapeutic agents
Anti-tumor antibodies used to clear tumor cells from bone marrow
Before autologous BM transplantation
Role of immune system in promoting tumor growth:
Innate immune system: inflammation
Macrophages (angiogenesis, tissue remodeling, free radicals/mutations)
Gastric cancer by Heliobacter pylori
Hepatocellular carcinoma by hepatitis B and C virus