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