Neuroendocrine neoplasms (NENs) are rare, heterogeneous and ubiquitous tumors 
commonly localized in the gastrointestinal tract, lung, and pancreas. The 
clinical behavior of NEN is highly unpredictable; in fact, low-grade cases can 
unexpectedly be associated with metastases. Currently, the 2010 WHO NEN 
classification employs histological differentiation and the proliferation index 
for grading tumors but fails to provide reliable prognostic and therapeutic 
indications. Therefore, there is an urgent need for a better characterization of 
G2/G3 NENs. Similar to several other tumors, NENs possess immune-escape 
mechanisms, but very little has yet been done to characterize this crucial 
aspect. There are no available data describing PD-L1 expression in these tumors. 
Here we provide, for the first time, evidence of PD-L1 tissue expression in 
gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). PD-L1 expression was 
significantly associated with a high-grade WHO classification (G3) (P<0.001) but 
not with gender, primary site, or lymph node status. The PD-L1 positivity rate 
and signal intensity are directly correlated (P<0.001) with a grade increase 
from G1 to G3. In particular in G3 cases, we observed a dichotomy between the 
morphology (WD- and PD-NENs) and Ki67. Moreover, our study demonstrated a 
significant association with the grade and PD-L1 expression levels in 
immune-infiltrating cells (P<0.001). In particular, G3 tumors are characterized 
by strong PD-L1 expression in both the tumor and infiltrating immune cells 
(P<0.001), reflecting an unfavorable environment for T-cell-mediated tumor 
aggression. These findings suggest that NENs might acquire resistance to immune 
surveillance by upregulating PD-L1 and inhibiting peritumoral and intratumoral 
infiltrating lymphocytes. Here we demonstrate that PD-L1 is currently the 
best-known biomarker for G3 NENs, becoming the new gold standard for G3 NEN 
discrimination. Furthermore, pharmacological approaches using anti-PD-1 
antibodies may become the logical choice for the treatment of G3 cases with a 
poor prognosis.