IFN- induced apoptosis dose-dependently in multiple cell lines, with a greater effect than IFN- at all time points. In WM9 cells, IFN-β led to increased levels of cyt c and increased activity of caspases 3, 8, and 9. IFN- induces TRAIL mRNA expression and XAF-1, which is a negative regulator of XIAP.
IFN- increases serum levels of antiangiogenic cytokines and decreases serum levels of pro-angiogenic cytokines. IFNs- decrease intracellular and secretory levels of VEGF in multiple cell lines, with a superior effect by IFN-. In human melanoma xenograft tumors, IFNs- similarly decrease microvessel density but IFN- has a superior effect over IFN- in decreasing lymphatic vessel density.
IFN- : tumor infiltration with CD4+ cells is not only required for the therapeutic effect of IFN-α but is also a consequence of treatment with IFN-. Use of IFN- as an adjuvant in the vaccination of metastatic melanoma patients has resulted in disease stabilization. Responders to IFN- therapy show restoration of immune responses to almost normal levels based on in vitro studies of T cell function and cytokine production. Metastases from IFN--treated patients show a low TNF-α staining score compared to those from untreated patients. IFN- is a potent stimulator of antimelanoma lytic activity via natural killer cells and cytotoxic T lymphocytes. In melanoma cell lines, IFN-α significantly enhances class I, but not class II, MHC expression. IFN-DCs may be promising adjuvants for cancer immunotherapy targeting melanoma. IFN- : treatment with IFN-β leads to increased T cell infiltration of interstitium and tumor nests. IFN-β has a greater effect than IFN- in inhibiting the TNF-α-mediated upregulation of IL-8, a growth factor for melanoma cells. IFN- augments NK cell-mediated cytotoxicity against melanoma cell lines. In melanoma cell lines, IFN- significantly enhances class I, but not class II, MHC expression, and augments expression of tumor-associated antigens.
Proinflammatory cytokines promote degradation of IFNAR1, leading to decreased tumor responsiveness to IFN. IFN- treatment leads to decreased detection of Stat3 homo- and heterodimers in atypical nevi as well as dephosphorylation of Stat3 protein in atypical nevi. Higher pretreatment pSTAT1/pSTAT3 ratios in tumor cells were associated with longer overall survival in stage IIIB patients. IFN signaling patterns in peripheral blood lymphocytes, as measured by STAT1 activation, can be used to select patients for high dose interferon therapy. IFN- maintenance therapy was shown to significantly increase overall and relapse-free survival in a clinical study of stage II-III melanoma patients.
