title: Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas.
abstract: B7-H3 and B7x are members of the B7 family of immune regulatory ligands that are thought to attenuate peripheral immune responses through co-inhibition. Previous studies have correlated their overexpression with poor prognosis and decreased tumor-infiltrating lymphocytes in various carcinomas including uterine endometrioid carcinomas, and mounting evidence supports an immuno-inhibitory role in ovarian cancer prognosis. We sought to examine the expression of B7-H3 and B7x in 103 ovarian borderline tumors and carcinomas and study associations with clinical outcome. Using immunohistochemical tissue microarray analysis on tumor specimens, we found that 93 and 100% of these ovarian tumors express B7-H3 and B7x, respectively, with expression found predominantly on cell membranes and in cytoplasm. In contrast, only scattered B7-H3- and B7x-positive cells were detected in non-neoplastic ovarian tissues. B7-H3 was also expressed in the endothelium of tumor-associated vasculature in 44% of patients, including 78% of patients with high-stage tumors (FIGO stages III and IV), nearly all of which were high-grade serous carcinomas, and 26% of patients with low-stage tumors (FIGO stages I and II; P<0.001), including borderline tumors. Analysis of cumulative survival time and recurrence incidence revealed that carcinomas with B7-H3-positive tumor vasculature were associated with a significantly shorter survival time (P=0.02) and a higher incidence of recurrence (P=0.03). The association between B7-H3-positive tumor vasculature and poor clinical outcome remained significant even when the analysis was limited to the high-stage subgroup. These results show that ovarian borderline tumors and carcinomas aberrantly express B7-H3 and B7x, and that B7-H3-positive tumor vasculature is associated with high-grade serous histological subtype, increased recurrence and reduced survival. B7-H3 expression in tumor vasculature may be a reflection of tumor aggressiveness and has diagnostic and immunotherapeutic implications in ovarian carcinomas.
authors.affiliation: Howard Hughes Medical Institute, Immunology Program, Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zang
authors.forename: Peggy S
authors.initials: PS
authors.lastname: Sullivan
authors.forename: Robert A
authors.initials: RA
authors.lastname: Soslow
authors.forename: Rebecca
authors.initials: R
authors.lastname: Waitz
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilton
authors.forename: Howard T
authors.initials: HT
authors.lastname: Thaler
authors.forename: Manonmani
authors.initials: M
authors.lastname: Arul
authors.forename: Susan F
authors.initials: SF
authors.lastname: Slovin
authors.forename: Joyce
authors.initials: J
authors.lastname: Wei
authors.forename: David R
authors.initials: DR
authors.lastname: Spriggs
authors.forename: Jakob
authors.initials: J
authors.lastname: Dupont
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D060887:B7 Antigens; D018122:B7-1 Antigen / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000401:mortality / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011971:Receptors, Immunologic / Q000378:metabolism*; D015996:Survival Rate; D046888:Tissue Array Analysis
chemical_list: D015703:Antigens, CD; D060887:B7 Antigens; D018122:B7-1 Antigen; D014408:Biomarkers, Tumor; C423237:CD276 protein, human; D011971:Receptors, Immunologic