A novel polyamine blockade therapy activates an anti-tumor immune response.
A novel polyamine blockade therapy activates an anti-tumor immune response.
复制标题
DOI：
10.18632/oncotarget.20493
复制
发表时间：
2017-10-13
期刊：
影响因子：
--
通讯作者：
Gilmour SK
中科院分区：
文献类型：
--
作者：
Alexander ET;Minton A;Peters MC;Phanstiel O 4th;Gilmour SK
大多数肿瘤维持高水平的多胺以支持其生长和存活。本研究探讨了多胺饥饿通过抑制多胺生物合成和阻断多胺向肿瘤中的上调输入而产生的抗肿瘤作用。我们证明，多胺阻断治疗（PBT）与DFMO和一种新的多胺转运抑制剂，三聚体PTI的共同治疗，显着抑制肿瘤的生长比治疗DFMO或三聚体PTI单独。PBT的抗肿瘤作用在其中CD 4+和CD 8 + T细胞被抗体耗尽的小鼠中丧失，这意味着PBT刺激T细胞依赖性的抗肿瘤免疫作用。PBT的抗肿瘤作用伴随着颗粒酶B+、IFN-γ+ CD 8 + T细胞的增加和免疫抑制性肿瘤浸润细胞的减少，包括Gr-1+ CD 11 B+髓源性抑制细胞（MDSC）、CD 4 + CD 25 + T细胞和CD 206 +F4/80+ M2巨噬细胞。用肿瘤特异性肽的刺激引起来自PBT处理的小鼠的脾细胞中抗原特异性IFN-γ分泌升高，表明PBT处理以肿瘤特异性方式刺激T细胞的活化。这些数据显示，用DFMO和三聚体PTI两者的组合治疗不仅剥夺了多胺成瘾性肿瘤细胞的多胺，而且减轻了肿瘤微环境中多胺介导的免疫抑制，从而允许活化杀肿瘤T细胞。
Most tumors maintain elevated levels of polyamines to support their growth and survival. This study explores the anti-tumor effect of polyamine starvation via both inhibiting polyamine biosynthesis and blocking the upregulated import of polyamines into the tumor. We demonstrate that polyamine blockade therapy (PBT) co-treatment with both DFMO and a novel polyamine transport inhibitor, Trimer PTI, significantly inhibits tumor growth more than treatment with DFMO or the Trimer PTI alone. The anti-tumor effect of PBT was lost in mice where CD4+ and CD8+ T cells were antibody depleted, implying that PBT stimulates an anti-tumor immune effect that is T-cell dependent. The PBT anti-tumor effect was accompanied by an increase in granzyme B+, IFN-γ+ CD8+ T-cells and a decrease in immunosuppressive tumor infiltrating cells including Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs), CD4+CD25+ Tregs, and CD206+F4/80+ M2 macrophages. Stimulation with tumor-specific peptides elicited elevated antigen-specific IFN-γ secretion in splenocytes from PBT-treated mice, indicating that PBT treatment stimulates the activation of T-cells in a tumor-specific manner. These data show that combined treatment with both DFMO and the Trimer PTI not only deprives polyamine-addicted tumor cells of polyamines, but also relieves polyamine-mediated immunosuppression in the tumor microenvironment, thus allowing the activation of tumoricidal T-cells.