B7-H3 is expressed in human hepatocellular carcinoma and is associated with tumor aggressiveness and postoperative recurrence

Abstract

B7-H3, a novel B7 family member, positively or negatively regulates T-cell responses. We investigated the clinical relevance and prognostic significance of B7-H3 in hepatocellular carcinoma (HCC). Western blotting showed B7-H3 upregulation in 17 of 24 (70.8 %) HCC tissues compared with nontumor liver tissues (p = 0.028). B7-H3 immunostaining on tissue microarrays containing 240 HCC patient samples indicated that 225 (93.8 %) tumors had aberrant B7-H3 expression, with strong intensity in 79 (32.9 %) cases, whereas B7-H3 expression in peritumor liver cells was weak in most cases (226; 94.2 %). Notably, patients with high/moderate tumor cell B7-H3 expression showed significantly poorer survival (p = 0.009) and increased recurrence (p = 0.002). After multivariable adjustment, high/moderate B7-H3 expression remained significant for an increased risk of recurrence (hazard ratio = 1.79; 95 % confidence interval = 1.19-2.70; p = 0.005). B7-H3 expression correlated with invasive phenotypes like vascular invasion and advanced tumor stage, and the metastatic potential of HCC cell lines. Flow cytometry showed that B7-H3 expression is inversely correlated with proliferation and interferon-γ production by infiltrating T cells. Interferon-γ stimulation significantly upregulated B7-H3 expression in HCC cells in vitro, implicating B7-H3 expression as a feedback mechanism to evade anti-tumor immunity. Importantly, the prognostic value of B7-H3 expression was validated in an independent cohort of 206 HCC patients. Collectively, our data suggest that B7-H3 was abundantly expressed in HCC and was associated with adverse clinicopathologic features and poor outcome. Thus, B7-H3 represents an attractive target for diagnostic and therapeutic manipulation in human HCC.

Soluble B7-H3 promotes the invasion and metastasis of pancreatic carcinoma cells through the TLR4/NF-κB pathway

“…Increasing evidence suggests that constitutive NF-κB activity plays a major role in the progression of malignant tumors capable of tissue invasion and metastasis20. In this study, we demonstrated that NF-κB activity was up-regulated by sB7-H3 in PCa cells and that increased NF-κB activity may account for the positive correlation between B7-H3-positive tumors and malignant tumorigenesis21. In addition, NF-κB regulated numerous gene products, including IL-8 and VEGF, which have been proven to promote tumor invasion and migration by inducing angiogenesis22.…”

B7-H3 expression in colorectal cancer: associations with clinicopathological parameters and patient outcome

“…While nuclear expression of B7-H3 in tumour cells so far has been reported by our group only, several authors have described the prognostic impact of tumour B7-H3 expression in various other cancer forms. The results are highly variable and even conflicting: Most reports indicate that high tumour B7-H3 level is associated with advanced disease and/or poor outcome [13, 14, 16, 17, 20, 33, 34]. Some investigators report no associations between tumour B7-H3 and prognosis [35, 36], and some that high tumour B7-H3 expression is associated with improved outcome [12, 15].…”

“…B7-H3, an immunoregulatory protein in the B7 family of T cell co-regulatory molecules [10, 11], is overexpressed in several different cancer forms including CRC [12–20]. The precise role of B7-H3 in tumour immunity is still ambiguous, as both T cell co-stimulatory and co-inhibitory effects have been demonstrated [21, 22].…”

Molecular Pathways: Targeting B7-H3 (CD276) for Human Cancer Immunotherapy

“…B7-H3 expression on lung cancer was associated with a lower number of tumor infiltrating lymphocytes (TILs) and with lymph node metastasis, suggesting a role for B7-H3 in immune evasion and tumorigenesis (30). Importantly, B7-H3 protein expression in tumors is known to be modulated by miR-29 (31), up-regulated upon IFN-γ stimulation (32) and potentially increased by Immunoglobulin-like transcript 4 signalling (33). …”