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

Abstract

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-γ. Additionally, the supernatants of tumor-associated macrophages (tMφs) 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, tMφs 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.

Tumor-expressed immune checkpoint B7x promotes cancer progression and antigen-specific CD8 T cell exhaustion and suppressive innate immune cells

“…However, analysis of cancerous tissues reveals an overexpression of B7x in a high proportion of patients’ tumors in various malignancies [ 35 ] with inductive stimuli for the expression not clear. Current literature suggests that the secretion of cytokines IL-10 and IFNγ from TAMs can up-regulate B7x on lung cancer and hematological malignancies like Non-Hodgkin Lymphoma (NHL) [ 27 , 28 ], however our studies did not confirm this after assaying several different human and murine tumors. Our aim was to evaluate changes in surface expression of B7x, but reports have demonstrated intracellular cytoplasmic and nuclear expression of B7x that have been affected under hypoxic conditions [ 36 , 37 ].…”

“…Understanding that B7x is a membranous protein that is rarely detected on normal human tissue and commonly up-regulated on the surface of cancer cells, we sought to assess the expression of B7x on a variety of human tumor cell lines and determine if common pro-inflammatory or anti-inflammatory cytokine stimulation could induce or enhance its expression. To evaluate this, we assayed four different human cancer cell lines (MDA MB 468 [breast], SKBR3 [breast], U2OS [osteosarcoma], OVCAR4 [ovary]) for their expression of endogenous B7x and stimulated each with the pro-inflammatory cytokine IFNγ, TNFα, or the anti-inflammatory cytokine IL-10 to evaluate potential change in expression following this stimulation based on current literature suggesting these cytokines regulate B7x on subsets of antigen-presenting cells (APCs) [ 27 – 30 ]. We observed that in the absence of stimulation, all tumor cell lines surveyed except for U2OS displayed various levels of B7x expression that did not change following cytokine stimulation.…”

B7-H4 overexpression is essential for early hepatocellular carcinoma progression and recurrence

“…To date, B7-H4 gene has been intensively studied in numerous tumors [ 28 , 29 ]. Previous studies have shown that high B7-H4 expression was significantly correlated with the size of tumor, depth of tumor infiltration, survival time, metastasis and recurrence [ 11 , 30 , 31 ]. Moreover, the level of B7-H4 in serum was also evaluated in various cancer patient populations, including HCC [ 19 , 20 ].…”

The influence of microenvironment on tumor immunotherapy

“…B7‐H4 is a tumor‐associated transmembrane protein that is upregulated on the surface of cancer cells and TAMs. Inhibition of B7‐H4 in NHL cells promoted T cell immunity and cytotoxic activity of NHL‐reactive T cells . The expression of B7‐H4 decreased CD4 + T cell responses via binding to semaphorin 3a .…”