Background
Digestive neuroendocrine neoplasms (NENs) are heterogeneous, encompassing a broad spectrum of neoplasms ranging from indolent well-differentiated neuroendocrine tumors (NETs) to highly aggressive neuroendocrine carcinomas (NECs). The PD-1/PD-L1 pathway plays a pivotal role in T cells activation and host immune response to cancer. PD-L1 expression in tumor and/or immune cells has been suggested as a prognostic biomarker in different type of cancers, allowing the identification of patients who can be treated with targeted checkpoint inhibitors. However, the prognostic role of PD-L1 expression in digestive NENs is still unclear.
Methods
We investigated PD-L1 expression using the SP263 antibody (Ventana Medical System) in 68 well- characterized digestive NENs: 32 NETs and 36 NECs. TPS and CPS PD-L1 scores, tumor infiltrating lymphocytes (detected using the anti-CD3, CD4, and CD8 antibodies), and mismatch repair (MMR) protein expression (detected using the anti-hMLH1, hMSH6, and hPMS2 antibodies) were evaluated. Immunohistochemical findings were correlated with clinicopathological features.
Results
PD-L1 scores TPS >1% and/or CPS >1 were observed in 5/32 NETs and 23/36 NECs (p: 0.05). The mean TPS score in positive cases was 6.3% and 14% in NETs and NECs, respectively. The CPS score was 4.8 and 7.91 in NETs and NECs, respectively. MMR-deficient neoplasms were more frequently observed in NECs than in NETs (2 NETs and 5 NECs, p: <0.05). No correlation between PD-L1 expression and survival or other clinicopathological parameters was found, including Ki67-proliferative index and MMR-deficiency. Intra- tumor immune infiltration was statistically more abundant in NECs than in NETs.
Conclusion
The heterogeneous expression of PD-L1 in NENs, with only a few positive cases among NETs, suggests that targeted checkpoint inhibitors therapy might have a potential role only in selected cases, mainly in NECs. T-cell infiltrate is more abundant in NECs than in NETs, supporting the possible application of immunological therapy in NECs.