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Table 2 Dual Effects of Cytokines on Tumor/Tumor Microenvironment

From: Peritoneal inflammation – A microenvironment for Epithelial Ovarian Cancer (EOC)

TGFβ IL6
• 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