CD47 expression and CD163+ macrophages correlated with prognosis of pancreatic neuroendocrine tumor

Abstract

Background Recent studies have suggested the important roles of CD47 and tumor-associated macrophages in the prognosis and immunotherapy of various human malignancies. However, the clinical significance of CD47 expression and CD163+ TAMs in pancreatic neuroendocrine tumor (PanNET) remains unclear. Methods In this study, 47 well-differentiated PanNET resection specimens were collected. CD47 expression and CD163+ macrophages were evaluated using immunohistochemistry and correlated with clinicopathologic properties. Results Positive CD47 staining was seen in all PanNETs as well as adjacent normal islets. Compared to normal islets, CD47 overexpressed in PanNETs (p = 0.0015). In the cohort, lymph node metastasis (LNM), lymphovascular invasion (LVI), and perineural invasion (PNI) were found in 36.2, 59.6, and 48.9% of the cases, respectively. Interestingly, PanNETs with LNM, LVI, or PNI had significantly lower H-score of CD47 than those without LNM (p = 0.035), LVI (p = 0.0005), or PNI (p = 0.0035). PanNETs in patients with disease progression (recurrence/death) also showed a significantly lower expression of CD47 than those without progression (p = 0.022). In contrast, CD163+ macrophage counts were significantly higher in cases with LNM, LVI, and PNI. Conclusions Our data suggest relative low CD47 expression and high CD163+ TAMs may act as indicators for poor prognosis of PanNETs.

Expression of CD47 in the pancreatic β‐cells of people with recent‐onset type 1 diabetes varies according to disease endotype

“…Our studies confirm recent evidence that human islet cells express abundant levels of CD47 15,19 and we reveal that it is present on both αand βcells. Analysis of the intensity of immunolabelling with an antiserum directed against CD47 implies that βcells express higher levels of CD47 than αcells in individuals without diabetes and this was true across all ages studied.…”

“…By analogy with the situation in other cell types (including some pancreatic neuroendocrine tumours), the increase in CD47 on islet α cells might be sensed by islet macrophages in a manner which then impairs their rate of phagocytosis. 14,15 However, this mechanism is unlikely to be of major significance in the development of type 1 diabetes since αcell numbers are not depleted by macrophage engulfment in this disease. Rather, it seems more likely that the increase in αcell CD47 occurs as an active response to minimise the rate of βcell death and we suggest that this may involve the ligation of SIRPα.…”

“…10,13,14 These mechanisms are subverted to advantage by certain tumour cells (including some pancreatic neuroendocrine tumours) which overexpress CD47 and thereby minimise their susceptibility to targeting and removal by cells of the innate immune system. [15][16][17] In addition, the mechanism may also be relevant to type 1 diabetes since enhanced signalling has been implicated in delaying the progression of insulitis in NOD mice where CD47 expression by islet cells is thought to exert a protective influence against the early macrophage infiltration seen in these animals. [18][19][20] A similar mechanism may also operate in humans early in the disease process although, overall, macrophages appear to play a much less significant role in human insulitis than in NOD mice.…”

Targeting CD47 for cancer immunotherapy

“…In addition to the CD47-SIRPα signaling pathway, significance of CD47 expression has been investigated in different malignancies. Association between CD47 expression, clinical characteristics and prognosis in patients with different malignancies, including advanced non-small cell lung cancer [ 1 ], gastric cancer [ 2 ], colorectal adenocarcinoma [ 3 ] and pancreatic neuroendocrine tumor [ 4 ] has been explored. For example, in patients with high-grade lung neuroendocrine tumors, the high expression of CD47 was strongly associated with a worse progression-free survival, especially in patients with a Ki-67 > 40% [ 1 ].…”

Elevated Flt3L Predicts Long-Term Survival in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

“…Early on, an association between higher numbers of tumor infiltrating CD3 + T cells and extended progression free survival was noted in resected intermediate grade pancreatic NET (panNET), while-conversely-a higher number of FoxP3 reactive regulatory T cells in resected liver metastases correlated to worse overall survival [12]. A negative impact on the clinical course of panNET was also proposed for tumor-associated macrophages (TAM) based on their positive correlation with poor disease-specific and disease-free survival [13,14] in G1 and G2 tumors. Recent immunohistological profiling of tumor microenvironment and tumor inflammatory features pointed towards an even more prominent role of immune-related features in high grade NEN [15,16].…”