TUMOR-IMMUNITÄT

A.K. Abbas, A.H. Lichtman, S. Pillai (6th edition, 2007)Cellular and Molecular ImmunologySaunders ElsevierChapter 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 immunocompromizedexperimental 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, p53Randomly mutated genes: TSTA´s (tumor-specific transplantation antigens)

Can be identified: biochemicalcDNA cloning

Tumor-associated: TAANormal cellular proteins aberrantly expressed

Tyrosinase - melanomas (enzyme melanin biosynthesis)Cancer/testis antigens: expressed testis and trophopblastsOncofetal antigens: developing fetal tissue

CEA: carcinoembryonic antigen - colo and many cancers, AFP: -fetoptotein - hepatocellular cancer and othersnot specific, can be induced inflammatory conditions

Altered glycolipid and glycoprotein antigens:gangliosides - in melanomasMucin-1 - O-linked carbohydrates

Tissue-specific differentiation antigens

Antigens of oncogenic viruses:

DNA-viruses:

EBV: Epstein-BarrHPV: papilloma

Animals:Papovaviruses: SC40, polyomaAdenoviruses

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 lymphocytesAdaptive:CD8+ cells:Clear for carcinogen-induced and virus-induced tumorsLess clear for spontaneous

But: tumor-specific CTL can be isolated from tumorsCross-presentation by professional APCs necessaryTo differentiate CD8+ cells to antitumor CTLs

Use of pulsed DCs in tumor therapy

CD4+ cells: not so clearCytokines for CTL developmentTNF and IFN- - macrophage activationAntibodies: complement, Fc receptor (macrophages, NK) Little evidence for in vivo effective humoral response

Evasion of immune responses:

Induction of tolerance:MMTVSV40T transgenicAnergy 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-Lmasking of cell surface: sialic acid containing mucopolysaccharides

Immunotherapies

Stimulation of active immune response

Vaccination:Killed tumor vaccines + adjuvantsPurified tumor antigensPulsed DCsCytokines and co-stimulator enhanced vaccinesDANN vaccinesViral vectors: tumor antigens + cytokines

Preventive versus therapeutic: hepatitis BHPV

Augmentation by costimulators: B7and cytokines: Il2, IL4, IFNs, GMCSF, TNF, IL12

Blocking inhibitory pathways: CTLA4 (autoimmunity !)

Bacillus Calmette-GuerinAnti-CD3

Passive immunotherapies:

LAK: from PBLs, IL2In mice impressive effectsIn patients wide individual variation

TILs: from inflammatory infiltrate

Graft versus leukemia effect

Anti-tumor antibodies - humanizedAnti-CD30Anti-HER2

Couped to toxins: ricin, diphteria toxinRadioisotopesAnti-tumor drugs

Anti-EGF: colorectal cancerAnti-VEGF: in combination with chemotherapeutic agents

Anti-tumor antibodies used to clear tumor cells from bone marrowBefore autologous BM transplantation

Role of immune system in promoting tumor growth:

Innate immune system: inflammationMacrophages (angiogenesis, tissue remodeling, free radicals/mutations)

Gastric cancer by Heliobacter pylori

Hepatocellular carcinoma by hepatitis B and C virus