M2 macrophage/microglial cells induce activation of Stat3 in primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is one of the most aggressive malignant lymphomas with a median survival of less than 20~40 months. Interest in signal transducer and activator of transcription 3 (Stat3) has increased during the past decade because Stat3 activation was found to contribute to tumor progression by inducing angiogenesis, immunosuppression, and metastasis. We previously demonstrated a significant correlation between Stat3 activation in tumor cells and infiltrating anti-inflammatory (M2) macrophages. Here, we focused on the phenotypes of infiltrating macrophages/microglial cells and Stat3 activation in PCNSL cells. The correlation of Stat3 activation or density of M2 macrophage infiltration with patient prognosis was also evaluated. We performed immunostaining for CD68, CD163, CD204, and pStat3 using paraffin-embedded PCNSL specimens obtained from 43 patients. CD163 and CD204 served as markers of the M2 phenotype. Dense infiltration of CD68(+) macrophages was found in all samples. High numbers of CD163(+) and CD204(+) M2 macrophages/microglial cells were observed in 29 and 25 cases, respectively. Stat3 activation in lymphoma cells was enhanced in the patients who showed denser infiltration of CD163(+) macrophages/microglial cells in tumor tissues. In vitro co-culture experiment to investigate cell-cell interactions between macrophages and lymphoma cells found that Stat3 in lymphoma cells was strongly activated by co-culture with macrophages. Numbers of CD68(+), CD163(+), and CD204(+) tumor-associated macrophages/microglial cells (TAMs) and Stat3 activation in lymphoma cells were not correlated with prognosis. However, because Stat3 involvement in tumor development was demonstrated in several malignant tumors, our present finding that cell-cell interactions of M2 macrophage/microglial cells with lymphoma cells induced Stat3 activation may provide novel insights into PCNSL pathogenesis.