Impaired immune responses in cancer patients have been associated with oxidative stress. Increased levels of reactive oxygen species released from activated, tumor-infiltrating macrophages or granulocytes may therefore constitute a hurdle for effective immunotherapy against cancer. In this study, we investigated functional consequences and molecular events in T cells exposed to low levels of oxidative stress. We observed that cytokine production of human PBMC, upon stimulation with an HLA-A*0201-restricted influenza peptide and nonspecific receptor cross-linking, was reduced after exposure to micromolar levels of H2O2. Functional impairment as measured by IFN-γ release occurred earlier and at lower doses of exogenously added H2O2 than required to induce apoptosis. This suggests that there is a dose window of oxidative stress leading to T cell unresponsiveness in the absence of apoptosis. The reduction of Th1 cytokines, induced by H2O2, was predominantly observed in memory/effector (CD45RO+) T cells and correlated with a block in NF-κB activation. IL-10 production was more profoundly influenced by low doses of H2O2 than IFN-γ, TNF-α, and IL-2. The influence of H2O2 on production of IL-10 was not significantly different between memory/activated and naive T cells. These observations suggest that Th1 and Th2 cytokines are differently regulated under conditions of oxidative stress. Taken together, these findings may explain why Ag-experienced, CD45RO+, T cells found in the tumor milieu are functionally suppressed.

These findings show that the inhibition of DC maturation by VEGF differs depending on the maturation status of the DCs.

Gastric cancers producing α-fetoprotein (AFP) have a poor prognosis and a high incidence of liver metastasis. Hepatocyte growth factor (HGF) and its receptor, c-Met, are known to induce mitosis and cell movement and to promote tumor progression. In the present study, c-Met and HGF expression in AFP-producing gastric cancer was compared with those gastric cancers that do not produce AFP. Twenty-six patients with AFP-producing gastric cancers [AFP(+)] and 26 patients stage-matched gastric cancers without AFP production [AFP(–)] were evaluated for c-Met and HGF expression and proliferating cell nuclear antigen-labelling index using immunohistochemical analysis. A higher frequency of c-Met expression was observed in the AFP(+) group than in the AFP(–) group (p < 0.01). A higher expression of c-Met might be one explanation for the poorer prognosis of AFP-producing gastric cancers.

A higher expression of VEGF-C might be one explanation for the poorer prognosis of AFP-producing gastric cancers.

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