Novel B7-H4-mediated crosstalk between human non-Hodgkin lymphoma cells and tumor-associated macrophages leads to immune evasion via secretion of IL-6 and IL-10

Non-Hodgkin lymphoma (NHL) is an incurable lymphoproliferative cancer, and patients with NHL have a poor prognosis. The present study explored the regulatory mechanism of expression and possible roles of the immunosuppressive B7-H4 molecule in human NHL. For functional studies, NHL-reactive T cell lines were generated via the isolation of allogeneic CD3(+) T cells from healthy donors and repeated in vitro stimulation with irradiated NHL cells isolated from patients. B7-H4 was found to be distributed in NHL cells and tissues, and its surface protein expression levels were further upregulated by the incubation of NHL cells with interleukin (IL)-6, IL-10, or interferon-gamma. Additionally, the supernatants of tumor-associated macrophages (tM phi s) upregulated B7-H4 surface expression by producing IL-6 and IL-10. B7-H4 expressed in NHL cells inhibited the cytotoxic activity of NHL-reactive T cells. Conversely, the inhibition of B7-H4 in NHL cells promoted T cell immunity and sensitized NHL cells to cytolysis. Furthermore, tM phi s induced B7-H4 promoted NHL cell evasion of the T cell immune response. In conclusion, this study shows that NHL-expressed B7-H4 is an important immunosuppressive factor that inhibits host anti-tumor immunity to NHL. Targeting tumor-expressed B7-H4 may thus provide a new treatment strategy for NHL patients.