Table 2 Dual Effects of Cytokines on Tumor/Tumor Microenvironment

• TGFβ + TGFβ RIII → TGFβ - RII + RI heterodimer → TGFβ RI - P + SMADs → SMAD - P → nucleus → initiates transcription

• TGFβ → in repression cell cycle genes or activation

• Repression involves activation of cycle dependent kinase inhibitors, blocks unbinding of pRb/E2F transcripts

• Other interactions include:

H-Ras (↓ RI & ↑ RII);

C-Myc (stimulates proliferation by repressing cdk inhibitors) associates w/E2F transcript factor complex

• TGFβ effect negated by disruption of signal pathway

• Alterations to the microenviroment

Tumor adhesion

Endothelial chemotaxis (proangiogenic)

Myofibroblast chemotaxis

• Immunosuppressive Effects

Adaptive

↓ MHC expression (targeting)

↓ Costimulatory Ag expression by DC

Blocks pre CTL → CTL

Suppresses TH1 cells - Shift to TH2

Induces apoptosis

Suppresses proliferative response to APCs

Innate Cells

Inhibits NK & MA activation

• ↑ TuC attachment migration

• Immune modulation (T-cell ↑)

• Interferes w/MA maturation to DC

• Proliferation thru P13-K activation

IL10

• ↓ MHC expression on TC

• ↓ Costimulatory Ag expression

• Suppress cytotoxic T-cell activation

• Inhibits IFNγ production

• Inhibits T-cell production