T-Cell Coregulatory Molecule Expression in Urothelial Cell Carcinoma: Clinicopathologic Correlations and Association with Survival

Abstract

Purpose: Aberrant expression ofT-cell coregulatory molecules has been investigated as a mechanism by which certain cancers may evade host immune surveillance.We evaluated expression of theT-cell coregulators B7-H1, B7-H3, and PD-1in urothelial cell carcinoma (UCC) of the bladder. Experimental Design: Immunohistochemistry for B7-H1, B7-H3, and PD-1was done onparaffinembedded sections from 318 consecutive patients with UCC who underwent radical cystectomy. Expression was correlated with clinicopathologic outcomes and postoperative survival. Results: B7-H3 was widely expressed in UCC, as 222 of 314 (70.7%) tumors showed positive staining. Expression of B7-H3 in UCC was significantly increased compared with adjacent, nontumor urothelium, as a median of 70% of tumor cells expressed B7-H3, compared with 20% of cells in nontumor specimens (P < 0.001). The increase in B7-H3 expression was independent of tumor stage (P = 0.13). Expression of B7-H1by UCC tumors (P < 0.001) and PD-1by tumorinfiltrating lymphocytes (P = 0.012) were significantly associated with increased pathologic stage. Patients who had received intravesical bacillus Calmette-Guerin before cystectomy tended to show increased expression of B7-H3 (P = 0.023) and PD-1 (P = 0.071) but were less likely to express B7-H1 (P = 0.027). Moreover, for the subset of patients with organ-confined disease (n = 167), B7-H1 expression independently predicted all-cause mortality after cystectomy (hazard ratio, 3.18; 95% confidence interval, 1.74-5.79; P < 0.001).Conclusions: B7-H3 is highly expressed in UCC across tumor stages, whereas B7-H1and PD-1 expression are associated with advanced disease. B7-H1 expression predicts mortality after cystectomy for patients with organ-confined tumors. These molecules may represent novel diagnostic or prognostic markers, as well as therapeutic targets, for patients with UCC.

Development of an Fc-Enhanced Anti–B7-H3 Monoclonal Antibody with Potent Antitumor Activity

“…22), ovarian (23), bladder (24), melanoma (25), and neuroectodermal (25) cancers and postulated to mediate immunomodulatory activity (26). Our immunohistochemical analysis confirmed and extended published data indicating B7-H3 is highly expressed across a variety of solid cancers.…”

Programmed death 1 is expressed in cutaneous infiltrates of mycosis fungoides and Sézary syndrome

“…Sections were blocked for endogenous peroxidase for 5 min using Endogenous Blocking Solution (Dako, Carpinteria, CA), washed twice, and incubated for 5 min in Serum-Free Protein Block (Dako), followed by incubation for 60 min in purified goat anti-human PD-1 antibody (R&D Systems, Minneapolis, MN) diluted 1:40. The specificity of the antibodies has been validated previously [16]. Immunohistochemical stains for CD3 (Novocastra, Bannockburn, IL), CD4 (Novocastra), and CD8 (Dako) were used to assist with the identification of the T-cell populations in all cases.…”

Humanized Affinity-matured Monoclonal Antibody 8H9 Has Potent Antitumor Activity and Binds to FG Loop of Tumor Antigen B7-H3

“…In more recent studies of patients with prostate cancer, tumor B7-H3 expression was strongly correlated with disease spread at time of surgery, increased risk of clinical cancer recurrence, and cancer-specific death (20,21). Moreover, tumor B7-H3 expression was correlated with poor patient survival in clear cell renal cell carcinoma, urothelial cell carcinoma (22,23), ovarian cancer (24), glioblastoma (25), osteosarcoma (26), pancreatic cancer (27), and neuroblastoma (28). A few earlier reports have also implicated a positive immunologic function of B7-H3; e.g.…”