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) (Po0.001) but
not with gender, primary site, or lymph node status. The PD-L1 positivity rate and signal intensity are directly correlated (Po0.001)
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 (Po0.001). In particular, G3 tumors are characterized by strong PD-L1 expression in both the tumor and
infiltrating immune cells (Po0.001), 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.
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