Tumor-infiltrating neutrophils predict poor survival of non-functional pancreatic neuroendocrine tumor.

OBJECTIVE: This study retrospectively characterized the immune infiltrating profile in non-functional pancreatic neuroendocrine tumors (NF-PanNETs). METHODS: Tumor tissues from the 109-patient Fudan cohort and 73-patient external validation set were evaluated by immunohistochemistry for nine immune cell types: tumor-infiltrating neutrophils (TINs), tumor-associated macrophages (TAMs), CD11c+ dendritic cells, anti-NCR1+ NK cells, CD4+ and CD8+ T cells, CD45RO+ memory T cells, FOXP3+ regulatory T cells (Tregs), and CD20+ B cells. RESULTS: TINs were primarily distributed in intratumoral area, dendritic cells and NK cells were scattered evenly in intratumoral and stromal areas, and Tregs were rarely detected. The remaining five cell types were primarily present in peritumoral stroma. Total TINs (P<0.001) and TAMs (P=0.002) increased as NF-PanNET-grade rose. Kaplan-Meier analyses showed that high intratumoral TINs, total TAMs, and stromal CD4+ T cell infiltration correlated with shorter recurrence-free survival (RFS, P=0.010, P=0.027, and P=0.035, respectively) and overall survival (OS, P=0.017, P=0.029, and P=0.045, respectively). Additionally, high intratumoral CD8+ T cell infiltration correlated with prolonged RFS (P=0.039). Multivariate Cox regression demonstrated that intratumoral TINs, WHO classification and AJCC8th TNM were independent factors for RFS (P=0.043, P=0.023, and P=0.029, respectively), whereas intratumoral TINs and WHO classification were independent factors for OS (P=0.010 and P=0.007, respectively). Furthermore, combination of TINs, WHO classification and AJCC8th TNM remarkably improved prognostic accuracy for RFS. Above results have been verified in the external validation set. CONCLUSION: Intratumoral TINs are an independent and unfavorable predictor of postoperative NF-PanNETs. A combination of TINs, WHO classification, and AJCC8th TNM could improve prognostic accuracy for RFS.