B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival

Abstract

B7-H4 is a recently described B7 family coregulatory ligand that has been implicated as an inhibitor of T cell-mediated immunity. Although expression of B7-H4 is typically limited to lymphoid cells, aberrant B7-H4 expression has also been reported in several human malignancies. To date, associations of B7-H4 with clinical outcomes for cancer patients are lacking. Therefore, we examined B7-H4 expression in fresh-frozen tumor specimens from 259 renal cell carcinoma (RCC) patients treated with nephrectomy between 2000 and 2003 and performed correlative outcome analyses. We report that 153 (59.1%) RCC tumor specimens exhibited B7-H4 staining and that tumor cell B7-H4 expression was associated with adverse clinical and pathologic features, including constitutional symptoms, tumor necrosis, and advanced tumor size, stage, and grade. Patients with tumors expressing B7-H4 were also three times more likely to die from RCC compared with patients lacking B7-H4 (risk ratio ‫؍‬ 3.05; 95% confidence interval ‫؍‬ 1.51-6.14; P ‫؍‬ 0.002). Additionally, 211 (81.5%) specimens exhibited tumor vasculature endothelial B7-H4 expression, whereas only 6.5% of normal adjacent renal tissue vessels exhibited endothelial B7-H4 staining. Based on these findings, we conclude that B7-H4 has the potential to be a useful prognostic marker for patients with RCC. In addition, B7-H4 represents a target for attacking tumor cells as well as tumor neovasculature to facilitate immunotherapeutic treatment of RCC tumors. Last, we demonstrate that patients with RCC tumors expressing both B7-H4 and B7-H1 are at an even greater risk of death from RCC.B7-H1 ͉ costimulation ͉ tumor biomarker ͉ immunotherapy ͉ kidney neoplasms

B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome

“…Interestingly, B7x was found to be preferentially expressed on tumor vasculature, suggesting a potential role for initiating or maintaining tumor angiogenesis (27). Because B7x has consistently demonstrated in vitro and in vivo inhibitory properties (8)(9)(10)22), it was postulated that B7x represents a promising target for antitumor immunotherapy in renal cell carcinoma (27). Consistent with this, we demonstrate that nearly all (99%) patients with prostate cancer have aberrant or ectopic expression of B7x.…”

“…Krambeck et al (27) recently evaluated B7x in 259 patients with renal cell carcinoma, demonstrating that tumor expression of B7x was associated with adverse pathologic features (including advanced tumor size, grade, and stage) and an increased risk of death from disease (27). Interestingly, B7x was found to be preferentially expressed on tumor vasculature, suggesting a potential role for initiating or maintaining tumor angiogenesis (27). Because B7x has consistently demonstrated in vitro and in vivo inhibitory properties (8)(9)(10)22), it was postulated that B7x represents a promising target for antitumor immunotherapy in renal cell carcinoma (27).…”

“…Transfection of B7-H3 into experimental tumor lines (P815 mastocytoma, Colon-26, and EL-4 lymphoma) has been reported to accelerate in vivo tumor rejection, supporting a net (22,25), uterus (26), and kidney (27). Krambeck et al (27) recently evaluated B7x in 259 patients with renal cell carcinoma, demonstrating that tumor expression of B7x was associated with adverse pathologic features (including advanced tumor size, grade, and stage) and an increased risk of death from disease (27). Interestingly, B7x was found to be preferentially expressed on tumor vasculature, suggesting a potential role for initiating or maintaining tumor angiogenesis (27).…”

“…Despite mRNA expression in various human tissues, immunohistochemistry (IHC) for B7x fails to reveal detectable protein expression in any healthy human organs (23). In stark contrast, aberrant expression of B7x has been observed in cancers of the breast (22,24), lung (16), ovary (22,25), uterus (26), and kidney (27). Thus, B7x, and perhaps B7-H3, have been proposed as potential therapeutic targets in human malignancy.…”

Higher preoperative serum levels of PD‐L1 and B7‐H4 are associated with invasive and metastatic potential and predictable for poor response to VEGF‐targeted therapy and unfavorable prognosis of renal cell carcinoma

“…In general, B7‐H4 positivity is associated with advanced cancer and poor survival, and this is also the case for RCC 11, 27. In an experimental model of lung metastasis, B7‐H4 expression by host cells was demonstrated to suppress tumor‐specific T‐cell responses and promote the infiltration of immunosuppressive T‐cell subsets into the lungs.…”