Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA.
Nat Immunol. 2023 Feb;24(2):239-254. doi: 10.1038/s41590-022-01388-8. Epub 2023 Jan 5.
Metastasis is the leading cause of cancer-related deaths and myeloid cells are critical in the metastatic microenvironment. Here, we explore the implications of reprogramming pre-metastatic niche myeloid cells by inducing trained immunity with whole beta-glucan particle (WGP). WGP-trained macrophages had increased responsiveness not only to lipopolysaccharide but also to tumor-derived factors. WGP in vivo treatment led to a trained immunity phenotype in lung interstitial macrophages, resulting in inhibition of tumor metastasis and survival prolongation in multiple mouse models of metastasis. WGP-induced trained immunity is mediated by the metabolite sphingosine-1-phosphate. Adoptive transfer of WGP-trained bone marrow-derived macrophages reduced tumor lung metastasis. Blockade of sphingosine-1-phosphate synthesis and mitochondrial fission abrogated WGP-induced trained immunity and its inhibition of lung metastases. WGP also induced trained immunity in human monocytes, resulting in antitumor activity. Our study identifies the metabolic sphingolipid-mitochondrial fission pathway for WGP-induced trained immunity and control over metastasis.
转移是癌症相关死亡的主要原因，髓系细胞在转移微环境中至关重要。在这里，我们通过用全β-葡聚糖颗粒（WGP）诱导训练免疫来探索重新编程前转移龛髓系细胞的意义。WGP 训练的巨噬细胞不仅对脂多糖而且对肿瘤来源的因子的反应性增加。WGP 的体内治疗导致肺间质巨噬细胞中出现训练免疫表型，从而抑制多种转移模型中的肿瘤转移和延长生存时间。WGP 诱导的训练免疫是由代谢产物 1-磷酸鞘氨醇介导的。WGP 训练的骨髓来源的巨噬细胞的过继转移减少了肿瘤肺转移。抑制 1-磷酸鞘氨醇合成和线粒体裂变会破坏 WGP 诱导的训练免疫及其对肺转移的抑制作用。WGP 还诱导人单核细胞中的训练免疫，从而产生抗肿瘤活性。我们的研究确定了 WGP 诱导的训练免疫和转移控制的代谢鞘脂-线粒体裂变途径。
