Role of Tumor-Associated Macrophages in the Clinical Course of Pancreatic Neuroendocrine Tumors (PanNETs)

Purpose: This study evaluated the potential role of immune cells and molecules in the pathogenesis and clinical course of pancreatic neuroendocrine tumors (PanNET). Experimental Design: Surgically resected PanNETs (N = 104) were immunohistochemically analyzed for Ki67 index, mitotic rate, macrophage, CD4(+) cells, and CD8(+) T-cell infiltration, as well as HLA class I, PD-L1, and B7-H3 expression. Results were correlated with clinicopathologic characteristics as well as with disease-free (DFS) and disease-specific (DSS) survival. Results: The median age of the 57 WHO grade 1 and 47 WHO grade 2 patients was 55 years. High intratumoral CD8(+) T-cell infiltration correlated with prolonged DFS (P = 0.05), especially when the number of tumor-associated macrophages (TAM) was low. In contrast, high peritumoral CD4(+) cell and TAM infiltration was associated with a worse DFS and DSS. PD-L1 and B7-H3 were expressed in 53% and 78% PanNETs, respectively. HLA class I expression was defective in about 70% PanNETs. HLA-A expression correlated with favorable DSS in PD-L1-negative tumors (P = 0.02). TAM infiltration (P = 0.02), WHO grade (P = 0.04), T stage (P = 0.01), and lymph node positivity (P = 0.04) were independent predictors of DFS. TAM infiltration (P = 0.026) and T stage (P = 0.012) continued to be predictors of DFS in WHO grade 1 PanNET patients. TAM infiltration was the sole independent predictor of DSS for WHO grade 1 and 2 patients (P = 0.02). Therefore, this biomarker may contribute to identifying WHO grade 1 patients with poor prognosis. Conclusions: TAM infiltration appears to be the most informative prognostic biomarker in PanNET. It may represent a useful immunotherapeutic target in patients with PanNET.