Expression and Prognostic Value of B7 Family Immune Checkpoints in Pancreatic Neuroendocrine Tumors

Context.-Pancreatic neuroendocrine tumors (PanNETs) are rare malignancies with heterogeneous clinical courses requiring novel prognosticators and therapies. B7 family molecules have an important role in various cancers; however, these have not been distinguished in PanNETs. Objective.-To investigate the expression and clinical significance of programmed death ligand-1 (PD-L1), programmed death ligand-2 (PD-L2), B7 homolog 3 (B7 -H3), B7 homolog 4 (B7-H4), and V-domain immunoglob-ulin suppressor of T-cell activation (VISTA) in 182 PanNETs (with a high proportion of functioning versus nonfunction-ing PanNETs: 51% versus 49%). Design.-Molecules were immunostained by using tissue microarrays from 182 patients with grade 1/2 PanNETs. VISTA-positive microvessel density (VISTA+ MVD) was evaluated in 4 high-power fields (HPFs) (3200) and mean count was calculated; immune cells with 1% or greater VISTA staining were considered positive. PD-L1 tumoral expression was considered positive in samples with 5% or more membranous staining. Tumoral VISTA, stromal PD-L1, PD-L2, B7-H3, and B7-H4 expres-sion were deemed positive if any staining was observed. Results.-VISTA+ MVD was high (>_10.8/HPF) in 45 patients (25%), while VISTA stained positively on immune and tumor cells in 121 (66%) and 0 patients, respectively. Positive PD-L1 tumoral and stromal expression was observed in 23 (13%) and 0 patients, with positive B7 -H3 expression in 76 (42%) and 98 (54%) patients, respectively, in these cells; PD-L2 and B7-H4 were not detected. PD-L1 positivity rate was high in functioning PanNETs. Stromal B7-H3 and high VISTA+MVD correlated with unfavorable clinicopathologic features. Moreover, high VISTA+ MVD was an independent predictor of shorter progression-free survival. Conclusions.-VISTA may serve as a prognosticator and immunotherapeutic target for patients with pancreatic neuroendocrine tumor (PanNET).