Induction of B7-H6, a ligand for the natural killer cell–activating receptor NKp30, in inflammatory conditions

Abstract

• B7-H6 transcripts, B7-H6 cell-surface expression, and sB7-H6 can be induced in inflammatory conditions in vitro and in vivo.• B7-H6 is expressed on proinflammatory CD141 CD16 1 monocytes in sepsis conditions and is linked to an increased mortality.B7-H6, a member of the B7 family of immunoreceptors, is as a cell-surface ligand for the NKp30-activating receptor expressed on natural killer cells. B7-H6 is not detected in normal human tissues at steady state but is expressed on tumor cells. However, whether B7-H6 can be expressed in other conditions remains unknown. We analyzed here the pathways that lead to the expression of B7-H6 in nontransformed cells. In vitro, B7-H6 was induced at the surface of CD14 1 CD16 1 proinflammatory monocytes and neutrophils upon stimulation by ligands of Toll-like receptors or proinflammatory cytokines such as interleukin-1b and tumor necrosis factor a. In these conditions, a soluble form of B7-H6 (sB7-H6) was also produced by activated monocytes and neutrophils. In vivo, B7-H6 was expressed on circulating proinflammatory CD14 1 CD16 1 monocytes in a group of patients in sepsis conditions, and was linked to an increased mortality. sB7-H6 was selectively detected in the sera of patients with gram-negative sepsis and was associated with membrane vesicles that co-sedimented with the exosomal fraction. These findings reveal that B7-H6 is not only implicated in tumor immunosurveillance but also participates in the inflammatory response in infectious conditions. This trial was registered at www.clinicaltrials.gov as #NTC00699868. (Blood. 2013;122(3):394-404)

NK cells and cancer: you can teach innate cells new tricks

“…90). B7-H6 is expressed preferentially on tumours, including leukaemias, lymphomas, melanomas and carcinomas 89 , but is induced on healthy Toll-like receptor (TLR)-activated myeloid cells 91 . NKp46-deficient (Ncr1 −/− ) mice have been reported to have an impaired ability to control growth of the PD1.6 lymphoma cell line 92 and metastasis of the B16 melanoma and Lewis lung carcinoma cell lines injected in the footpad or in the tail vein 93 , although NKp46 ligands on these tumours have not been identified.…”

Metalloprotease-Mediated Tumor Cell Shedding of B7-H6, the Ligand of the Natural Killer Cell–Activating Receptor NKp30

“…The interaction of B7-H6 on tumor cells with NKp30 on NK cells leads to efficient NK-cell activation and target cell killing (9). To date, B7-H6 expression was found on tumor cell lines or monocytes and neutrophils after inflammatory stimulation and has not been detected on healthy cells (9,11,12). So far, mechanisms regulating B7-H6 expression on tumor cells are still poorly explored.…”

Clinical significance of novel costimulatory molecule B7-H6 in human breast cancer

“…B7-H6 binds to NKp30, triggering antitumor NK cell cytotoxicity and cytokine secretion, thus B7-H6 functions as a tumor-induced self-molecule that alerts the innate immune system to cellular transformation (11,12). Previous studies have investigated the association between B7-H6 expression and numerous types of tumor, including 65 cases of lung cancer, 60 cases of gastric cancer and 110 cases of human ovarian cancer (12)(13)(14).…”

“…As specific niches of B7 family members continue to be dissected, their diagnostic and therapeutic potential in tumors is becoming more apparent (6,7), and this was highlighted in 2011 by the US Food and Drug Administration approval of an antibody targeting programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 in cancer (8,9). The ability to successfully target cell cycle checkpoint regulators has since led to multiple clinical trials investigating antibodies targeting the signaling pathway that the B7 family participate in (10).B7-H6 binds to NKp30, triggering antitumor NK cell cytotoxicity and cytokine secretion, thus B7-H6 functions as a tumor-induced self-molecule that alerts the innate immune system to cellular transformation (11,12). Previous studies have investigated the association between B7-H6 expression and numerous types of tumor, including 65 cases of lung cancer, 60 cases of gastric cancer and 110 cases of human ovarian cancer (12)(13)(14).…”