IMMUNE PROFILING IDENTIFIES IMMUNOSUPPRESSIVE CELLS IN PANCREATIC NEUROENDOCRINE TUMORS (PNETS)

BACKGROUND: Although pancreatic neuroendocrine tumors (PNETs) are rare, their incidence has been on the rise. There are few effective systemic chemotherapies for PNETs and immunotherapy for this disease has not been extensively studied. A subset of patients have demonstrated response to immune checkpoint inhibitor therapy, but the clinical and pathological characteristics that predict response to immunotherapy is unknown. AIM: To characterize the tumor microenvironment (TME) of PNETs and identify immunosuppressive cells as targets for drug treatment. METHODS: PNETs (n=90) were collected at the time of surgery, formalin-fixed paraffin-embedded (FFPE) tissue was processed into 2-mm sections to create a tissue microarray of de-identified tissue. The TME was analyzed using multiplex immunofluorescence (IF) for T cells (CD3), B cells (CD19), neutrophils (CD66B), macrophages (CD68/CD163), regulatory T cells (CD3&FOXP3), stromal myofibroblasts (a-SMA) and epithelial tumor cells (PanCK). Macrophages were further characterized as M1 (CD68 & HLA-DR) or M2 macrophages (CD163 & CD206), which are roughly thought to be anti-tumoral or pro-tumoral, respectively. Halo software was used for cell quantification. RESULTS: The grade of the tumors was Grade 1 (48%), Grade 2 (37%), Grade 3 (4%) and not reported (10%). The frequency of immune cells was higher in the stromal regions of the tumor than in epithelial regions. Tumor infiltration by macrophages was significantly higher than by T cells, regulatory T cells, B cells, or neutrophils. Grade 1 tumors had more macrophages, T cells, and regulatory T cells than did grade 2 tumors (p<0.02). M2 macrophages were 4-fold more prevalent than M1 macrophages (p<0.0001). CONCLUSION: Well-differentiated PNETs have a complex tumor microenvironment that is dominated by macrophages. The immune cells mostly reside in the stroma of PNETs, which suggests that therapies aimed at modulating immune cell migration may synergize with immune checkpoint inhibitor therapy.