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

Abstract

Abstract. B7 homolog 6 (B7-H6), a member of the B7 family, is as a cell-surface ligand for natural cytotoxicity triggering receptor 3, which is expressed on natural killer cells. It has previously been reported that B7-H6 is undetectable in normal human tissues but is expressed on tumor cells. However, there are few studies focusing on the clinical significance of B7-H6 expression in human carcinoma, with the exception of three studies on ovarian, lung and gastric cancer. The present study investigated the expression of B7-H6 protein in pathologic tissue samples from 305 patients with breast cancer using immunohistochemistry. A high B7-H6 expression level was identified in tissues from 32.13% of patients with breast cancer. These patients were revealed to also exhibit a high expression level of human epidermal growth factor receptor 2, a shorter survival time and a higher rate of lymph node metastasis. Furthermore, the expression level of B7-H6 was not associated with patient age, breast cancer subtype, tumor size, tumor location or estrogen receptor expression. The results of the present study revealed that higher B7-H6 expression level in breast cancer tissues was positively associated with tumor progression. This indicates that B7-H6 is associated with the progression and immunoevasion of human breast cancer; however, the molecular mechanisms underlying this potential effect require further investigation. IntroductionB7 homolog 6 (B7-H6), a novel member of the B7 family, was identified on tumor cell surfaces in 2009 (1). B7-H6 has sequence homology with other B7 molecules and similar to other members of the B7 family, B7-H6 contains two extracellular immunoglobulin (Ig) domains; however, the receptor for B7-H6, located on natural killer (NK) cells, was not consistent with other B7 family member receptors, which are located on activated T cells. The receptor for B7-H6 is natural cytotoxicity triggering receptor 3 (NKp30) (1-3). NK cells are large granular lymphocytes that produce chemokines and cytokines, and participate in the inflammatory and adaptive immune response (4). NK cells are also an important part of the innate immune system as they directly kill transformed and virally infected cells (5).B7 family members serve an essential role in regulating the immune response against transformed cells through a variety of mechanisms (6). 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-ind...

The prognostic value of B7-H6 in esophageal squamous cell carcinoma

“…We also found that the expression level of B7-H6 correlated with T stage and lymphatic metastasis status, which demonstrated that B7-H6 expression might be a marker to identify the T stage and lymphatic metastasis status of esophageal squamous cell carcinoma. This result is similar to the findings of studies in gastric carcinoma, ovarian cancer, non-small cell lung cancer, astrocytoma, breast cancer and other cancers (14,15,17,(34)(35)(36). In addition, Cox regression analysis and the log-rank test revealed that B7-H6 expression level was independent prognostic factor for ESCC.…”

Deficient Natural Killer Cell NKp30‐Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma

“…The NKp30 receptor recognizes the human leukocyte antigen–B‐associated transcript 3, the human cytomegalovirus pp65 tegument protein, and the cell surface protein B7 homolog 6 (B7‐H6), a member of the B7 family of receptors . Interestingly, B7‐H6 is not expressed by normal human tissues but is selectively expressed on stressed cells, including both solid and transformed blood cells, which can up‐regulate B7‐H6 expression and enhance tumor susceptibility to NK cell lysis . The interaction of B7‐H6 on tumor cells with NKp30 on NK cells results in interferon‐γ (IFN‐γ) production and tumor cell killing, suggesting that the NKp30–B7‐H6 axis can be exploited for cancer immunotherapy .…”

“…(11)(12)(13) Interestingly, B7-H6 is not expressed by normal human tissues but is selectively expressed on stressed cells, including both solid and transformed blood cells, which can up-regulate B7-H6 expression and enhance tumor susceptibility to NK cell lysis. (14)(15)(16) The interaction of B7-H6 on tumor cells with NKp30 on NK cells results in interferon-γ (IFN-γ) production and tumor cell killing, suggesting that the NKp30-B7-H6 axis can be exploited for cancer immunotherapy. (17) In addition, B7-H6 can also be induced as a stress protein by viral infections closely linked to carcinogenesis, such as hepatitis B virus (HBV).…”

The prognostic value of B7-H6 in esophageal squamous cell carcinoma

“…This result is similar to the findings of studies in gastric carcinoma, ovarian cancer, non-small cell lung cancer, astrocytoma, breast cancer and other cancers. (14,15,17,(20)(21)(22) In addition, Cox regression analysis and the log-rank test revealed that tumour size, lymphatic metastasis status and B7-H6 expression were independent prognostic factors for esophageal squamous cell carcinoma. Patients with a tumour size greater than or equal to 3.0 cm, high B7-H6 expression or lymphatic metastasis had significantly worse survival than those with a tumour size less than 3.0 cm, low B7-H6 expression or no lymphatic metastasis, respectively, suggesting that a tumour size greater than or equal to 3.0 cm, high B7-H6 expression and lymphatic metastasis are predictors of a poor prognosis.…”

“…This result is similar to data from other researchers. (15,21,22) Thus, B7-H6 may be regarded as a possible biomarker for predicting the OS time of esophageal squamous cell carcinoma patients, and also as an independent prognostic index for patients.In the past three years, some studies of the knockdown of B7-H6 expression in tumours have been carried out (16,23,24) and indicated that B7-H6 may be a potential therapeutic target in several human cancers. Therefore, it is believed that further studies on the expression of B7-H6 at the gene level and the knockdown of B7-H6 expression will also have certain clinical value in determining the prognosis of esophageal squamous cell carcinoma patients.…”