诱导“诱导转移的巨噬细胞”的训练免疫以控制肿瘤转移

SCI  21 January 2022

Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis

 (Nat Immunol, IF: 31.25)

Ding Chuanlin,Shrestha Rejeena,Zhu Xiaojuan et al. Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis.[J] .Nat Immunol, 2023, undefined: undefined.

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 immunitywith whole beta-glucan particle (WGP). WGP-trained macrophages had increased responsiveness not only tolipopolysaccharide 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，髓细胞在转移微环境中至关重要。在这里，我们探索了通过用整个β-葡聚糖颗粒(WGP)诱导训练免疫来重编程转移前小众髓样细胞的意义。WGP训练的巨噬细胞不仅对多糖反应性增强，而且对肿瘤衍生因子反应性增强。WGP体内治疗导致肺间质巨噬细胞的免疫表型训练，从而抑制肿瘤转移和延长多种小鼠转移模型的生存期。WGP诱导的训练免疫是由代谢物鞘氨酰-1-磷酸介导的。WGP培养的骨髓巨噬细胞过继转移减少肿瘤肺转移。阻断鞘氨脂-1-磷酸合成和线粒体裂变可消除WGP诱导的训练免疫及其对肺转移的抑制作用。WGP还能诱导人单核细胞的训练免疫，从而产生抗肿瘤活性。我们的研究确定了WGP诱导的训练免疫和控制转移的代谢性鞘脂-线粒体裂变途径。