Immunity to tumors - Tor Vergatadidattica.uniroma2.it/.../corsi/145880/5._Tumor_immunology_.pdf ·...
Transcript of Immunity to tumors - Tor Vergatadidattica.uniroma2.it/.../corsi/145880/5._Tumor_immunology_.pdf ·...
Immunity to tumors
Experimental evidence for tumor immunity Memory and Specificity
Tumor antigens - tumor-specific antigens (TSA): products of
- mutated oncogenes and oncosuppressors - other mutated proteins - oncogenic viruses (EBV, papillomavirus, HTLV-1)
- tumor-associated antigens (TAA)
- self proteins, normally expressed at undetectable levels, but overexpressed in tumors tirosinase → melanomas c-ERB-2 → mammary, ovary carcinomas
- oncofetal antigens, normally expressed during fetal life:
carcinoembryonal antigen (CEA/CD66) → colon, liver, pancreas alphafetoprotin (AFP) → liver MAGE → melanomas - others (used as targets for immunotherapy) CD10, CD20 → B cell lymphomas, leukemias Ig idiotypes → B cell lymphomas, leukemias gangliosides (GD2, GD3, GM2) → melanomas
Types of tumor antigens recognized by T cells
TSA
TSA
TSA
TAA
Identification of tumor antigens (→ vaccine development)
1 of 2
Identification of tumor antigens
2 of 2
Cells involved in anti-tumor responses Innate immunity - NK cells
low MHC NKG2D → MICA CD16 (FcγR1) → Antibody-Dependent Cellular Cytotoxicity activation with IL-2/IL-12 → LAK (Lymphokine-Activated Killers)
- macrophages (direct killing, IFNγ → TNF)
Adoptive immunity - CTL, directly activated by TSA or TAA + MHC, or
activated by dendritic cells that phagocyte tumor cells → presentation to CD4 T cells on MHC class II (cytokine release) and to CD8 T cells on MHC class I (cross-priming)
Induction of tumor-specific CTLs
Tumor escape
Tumor escape
Spontaneous tumors are rarely immunogenic → tumor editing
Tumor escape, tumor editing - tumor antigens can induce tolerance (in the absence of co-stimulation) - production of TGFβ → activation of Treg → IL-10, suppression - antigen loss→ no recognition - MHC loss→ no recognition - FasL expression → killing of attacking CTL - blockade of the apoptotic machinery
Tumor antigens as vaccines
Tumor antigens as vaccines
Tumor cells as vaccines and immunostimulators
Vaccination is effective to prevent tumors, not to cure – and mostly for virus-induced tumors
Cytokine-transfected tumor cells as immunotherapy
Systemic anti-tumor cytokine therapy
FDA-approved anti-tumor mAbs for therapy
Anti-CTLA-4 mAbs to prevent inhibition of CD28 – B7 interactions
Anti-idiotype mAbs to kill B lymphocytes in B cell lymphoma/leukemias
Anti-VEGF mAbs to prevent angiogenesis in tumors
Anti-cERB2 mAbs to kill carcinoma cells
Antibodies can be conjugated with toxins (ricin, Pseudomona toxin), chemotherapics (adriamycin)
or radioisotopes (gamma radiating)
Adoptive cellular therapy LAK (lymphokine-activated killers)
LAK