B7-H3 Ligand Expression by Prostate Cancer: A Novel Marker of Prognosis and Potential Target for Therapy

Abstract

B7 coregulatory ligands can be aberrantly expressed in human disease. In the context of cancer, these ligands may act as antigen-specific inhibitors of T-cell-mediated antitumoral immunity. We recently reported that B7-H1 expression by carcinomas of the kidney and bladder portends aggressive disease and diminished survival. The expression of these proteins in prostate cancer, however, has not been investigated. We evaluated B7-H3 and B7-H1 protein expression in the pathologic specimens of 338 men treated for clinically localized prostate cancer between 1995 and 1998 with radical retropubic prostatectomy. Expression levels of B7-H3 in prostate cancer were correlated with pathologic indicators of aggressive cancer as well as clinical outcome. We report that B7-H3 is uniformly and aberrantly expressed by adenocarcinomas of the prostate, high-grade prostatic intraepithelial neoplasia, and four prostate cancer cell lines, whereas B7-H1 is rarely expressed. B7-H3 is expressed by benign prostatic epithelia, although at a more reduced level relative to neoplastic tissue. Increasing levels of B7-H3 intensity correlate with worsening clinicopathologic features of prostate cancer. Marked B7-H3 intensity, present in 67 (19.8%) specimens, confers a >4-fold increased risk of cancer progression after surgery (risk ratio, 4.42; P < 0.001). A survey of normal tissues revealed that B7-H3 is expressed within the liver, urothelium, and fetal kidney. In summary, B7-H3 is aberrantly expressed in all prostate cancers and represents an independent predictor of cancer progression following surgery. Moreover, B7-H3 encompasses a novel diagnostic and potential therapeutic target for the clinical management of prostate cancer and, perhaps, other malignancies as well. [Cancer Res 2007;67(16):7893-900]

Clinical importance of B7-H3 expression in human pancreatic cancer

“…These clinical data suggested that tumour B7-H3 might function as a negative regulator in pancreatic cancer. This might be consistent with several previous reports in other malignancies, including lung and prostate cancers (Castriconi et al, 2004;Sun et al, 2006;Roth et al, 2007;Zang et al, 2007). However, there was no significant difference in post-operative prognosis as a result of tumour B7-H3 expression.…”

“…These data suggested that tumour-associated B7-H3 expression might promote immune response as a positive regulator. By sharp contrast, the negative role of B7-H3 expression has been reported in lung and prostate cancers Roth et al, 2007;Zang et al, 2007). In nonsmall-cell lung cancer, B7-H3 expression was inversely correlated with the number of tumour-infiltrating lymphocytes, and a high B7-H3 expression was more common in patients with lymph node metastasis .…”

“…B7-H3 expression has been identified in several tumour cell lines and in actual human tumour specimens, including gastric cancer, non-small-cell lung cancer, and prostate cancer Wu et al, 2006;Roth et al, 2007;Zang et al, 2007). Several murine studies have shown that introduction of B7-H3 in tumour cells and tissues by various methods activates tumour-specific immunocompetent cells and promotes anti-tumour response, thereby leading to rapid tumour regression, reduction of metastasis, and prolongation of animal survival (Sun et al, 2003;Luo et al, 2004Luo et al, , 2006Lupu et al, 2006Lupu et al, , 2007.…”

“…In nonsmall-cell lung cancer, B7-H3 expression was inversely correlated with the number of tumour-infiltrating lymphocytes, and a high B7-H3 expression was more common in patients with lymph node metastasis . Furthermore, a strong intensity for B7-H3 was significantly correlated with disease spread at the time of surgery, as well as with increased risk of recurrence and poor prognosis in prostate cancer (Roth et al, 2007;Zang et al, 2007). In addition, 4Ig-B7-H3 (B7-H3 protein with four-Ig-like domains) was identified in advanced stage neuroblastoma and has been shown to exert a protective effect on neuroblastoma cells from NK-mediated lysis (Castriconi et al, 2004).…”

Functional Analysis of B7-H3 in Colonic Carcinoma Cells

“…For example, B7-H3 is over-expressed by all six non-small-cell lung cancer (NSCLC) cell lines on both mRNA and protein level. (Sun et al, 2006;Xu et al, 2010) (Roth et al, 2007;Zang et al, 2007;Yuan et al, 2011). Also in breast cancer, B7-H3 mRNA expression was detected 39% in primary breast tumors but not in normal breast tissues (Ahmed, 2010).…”