关键词: 肿瘤相关巨噬细胞, 巨噬细胞极化, 前列腺癌, PD-1 抑制剂 

Abstract: Objective To investigate the effect of PD-1 inhibitors on tumor-associated macrophage (TAM) polarization and proliferation and invasion of prostate cancer, and the related mechanisms. Methods The tumor and adjacent tissues of 25 patients with prostate cancer were collected. The expression levels of programmed death factor 1 ( PD-1), macrophage mannose receptor (CD206) and signal transduction and transcription activator 6 ( STAT6) were detected by realtime quantitative fluorescent PCR ( qRT-PCR), and Spearman correlation analysis was then performed. Human monocytic leukemia cells (THP-1) were induced to TAM, during which the PD-1 inhibitor Camrelizumab or the STAT6 inhibitor AS1517499 was added. The above cells were divided into 4 groups of M0, M0 + Camrelizumab, TAM and TAM + Camrelizumab, or 4 groups of M0, M0 + AS1517499, TAM and TAM + AS1517499. The expression levels of STAT6 and CD206 were detected by qRT-PCR and Western blotting, and the concentration of interleukin-13 ( IL-13 ), transforming growth factor-β ( TGF-β) and nitric oxide synthase ( iNOS) were detected by enzyme-linked immunosorbent assay ( ELISA). Each group of cells were co-cultured with prostate cancer cells (DU145). The proliferation level of DU145 cells were detected by CCK8, and the invasion level were detected by Transwell assay. Results The expression levels of PD-1, CD206 and STAT6 in the prostate tumor tissues were elevated when compared with those in the adjacent tissues, and the expressions of PD-1, STAT6 were positively correlated with the expression of CD206 in tumor tissues respectively (all P< 0. 05). The expression levels of CD206 and STAT6 and the secretion levels of IL-13 and TGF-β were increased, while the level of iNOS was decreased in the TAM group, when compared with those in the M0 group, and the proliferation and invasion ability of DU145 cells co-cultured with the TAM were increased ( all P < 0. 05). The expression levels of CD206 and STAT6 were reduced in the TAM + Camrelizumab group when compared with the TAM group, in addition, the secretion levels of IL-13 and TGF-β were also decreased, the secretion levels of iNOS was increased. Meanwhile, the proliferation and invasion ability of DU145 cells cocultured with cells in the TAM + Camrelizumab group were decreased (all P < 0. 05). The cells in the TAM + AS1517499 group also had the reduced expression level of CD206, decreased secretion levels of IL-13 and TGF-β and increased secretion levels of iNOS when compared with those in the TAM group. Meanwhile, the proliferation and invasion ability of DU145 cells co-cultured with cells in the TAM + AS1517499 group were decreased (all P < 0. 05). Conclusion PD-1 inhibitors reduce the proliferation and invasion of prostate cancer cells by inhibiting the polarization of macrophages to TAM, which may be achieved by inhibiting the STAT6 signaling pathway in macrophages

Key words: tumor-associated macrophages, macrophage polarization, prostate cancer, programmed death-1 inhibitors