Re-education of Tumor-Associated Macrophages by CXCR2 Blockade Drives Senescence and Tumor Inhibition in Advanced Prostate Cancer
Re-education of Tumor-Associated Macrophages by CXCR2 Blockade Drives Senescence and Tumor Inhibition in Advanced Prostate Cancer
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DOI：
10.1016/j.celrep.2019.07.068
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发表时间：
2019-08-20
期刊：
影响因子：
8.8
通讯作者：
Alimonti, Andrea
中科院分区：
文献类型：
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作者：
Di Mitri, Diletta;Mirenda, Michela;Alimonti, Andrea
肿瘤相关巨噬细胞（TAM）是支持肿瘤发生的肿瘤微环境的主要组成部分。TAM再教育已被提出作为促进肿瘤抑制的策略。然而，这种方法是否适用于前列腺癌尚不清楚。在这里，我们发现Pten无效的前列腺肿瘤被表达C-X-C趋化因子受体2（CXCR 2）的TAM强烈浸润，并且通过CXCL 2激活该受体使巨噬细胞向抗炎表型极化。值得注意的是，选择性拮抗剂对CXCR 2受体的药理学阻断促进了TAM向促炎表型的再教育。引人注目的是，在Pten（pc-/-）; Trp 53（pc-/-）小鼠中输注的CXCR 2敲除单核细胞分化为释放肿瘤坏死因子α（TNF-α）的促炎性巨噬细胞，导致衰老和肿瘤抑制。从机制上讲，由于TNFR 1的增加，PTEN缺陷的肿瘤细胞易受TNF-α诱导的衰老的影响。我们的研究结果确定了TAM作为前列腺癌的靶点，并描述了一种基于CXCR 2阻断的治疗策略，以利用巨噬细胞的抗肿瘤潜力对抗这种疾病。
Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment supporting tumorigenesis. TAMs re-education has been proposed as a strategy to promote tumor inhibition. However, whether this approach may work in prostate cancer is unknown. Here we find that Pten-null prostate tumors are strongly infiltrated by TAMs expressing C-X-C chemokine receptor type 2 (CXCR2), and activation of this receptor through CXCL2 polarizes macrophages toward an anti-inflammatory phenotype. Notably, pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the re-education of TAMs toward a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in Pten(pc-/-); Trp53(pc-/-) mice differentiated in tumor necrosis factor alpha (TNF-alpha)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, PTEN-deficient tumor cells are vulnerable to TNF-alpha-induced senescence, because of an increase of TNFR1. Our results identify TAMs as targets in prostate cancer and describe a therapeutic strategy based on CXCR2 blockade to harness anti-tumorigenic potential of macrophages against this disease.