Fu Chenghao, Lu Yao, Zhang Yiwei, Yu Mingxi, Ma Shiliang, Lyu Shuxia
College of Food Science Shenyang Agricultural University Shenyang China.
College of Bioscience and Biotechnology Shenyang Agricultural University Shenyang China.
Food Sci Nutr. 2021 Aug 5;9(10):5517-5526. doi: 10.1002/fsn3.2510. eCollection 2021 Oct.
Immune-based interventions are the most promising approach for new cancer treatments to achieve long-term cancer-free survival. However, the expansion of myeloid-derived suppression cells (MDSCs) attenuates the therapeutic potential of immunotherapy. We recently showed that CD205+ granulocytic MDSCs (G-MDSCs), but not T cells, are sensitive to glucose deficiency. Intermittent fasting (IF) may inhibit the growth of malignant cells by reducing serum glucose levels, but little is known regarding the influence of IF on MDSC expansion. Herein, we observed that IF selectively inhibited splenic accumulation of CD205+ G-MDSCs in a 4T1 and 4T07 transplant murine breast cancer model. The efficiency of IF in suppressing tumor growth was comparable to that of docetaxel. Further examination revealed that CXCR4 expression was concentrated in CD205+ subsets of tumor-induced G-MDSCs. Downregulation of CXCR4 correlated with a reduction in CD205+ G-MDSC trafficking from bone marrow to the spleen under IF treatment. In addition, ex vivo culture assays showed that glucose deficiency and 2-deoxy-D-glucose (2DG) treatment selectively induced massive death of splenic CD205+ G-MDSCs. Interestingly, 2DG emulated the phenomena of IF selectively suppressing the accumulation of CD205+ G-MDSCs in the spleen, upregulating cleaved caspase 3 in the tumor, downregulating Ki67 in the lung, and retarding the growth of transplanted 4T1 and 4T07 murine breast tumors. These findings suggest that IF inhibited cell trafficking through the downregulation of CXCR4 and induced apoptosis by altering glucose metabolism; this, suppressed the accumulation of tumor-induced splenic CD205+ G-MDSCs and in turn enhanced antitumor immunity.
基于免疫的干预措施是实现长期无癌生存的新型癌症治疗最具前景的方法。然而，髓系来源的抑制细胞（MDSCs）的扩增会削弱免疫疗法的治疗潜力。我们最近发现，CD205⁺ 粒细胞性 MDSCs（G-MDSCs）而非 T 细胞对葡萄糖缺乏敏感。间歇性禁食（IF）可能通过降低血清葡萄糖水平来抑制恶性细胞的生长，但关于 IF 对 MDSC 扩增的影响知之甚少。在此，我们观察到在 4T1 和 4T07 移植性小鼠乳腺癌模型中，IF 选择性地抑制了脾脏中 CD205⁺ G-MDSCs 的积累。IF 在抑制肿瘤生长方面的效率与多西他赛相当。进一步检查发现，CXCR4 表达集中在肿瘤诱导的 G-MDSCs 的 CD205⁺ 亚群中。在 IF 治疗下，CXCR4 的下调与 CD205⁺ G-MDSCs 从骨髓向脾脏的转运减少相关。此外，体外培养试验表明，葡萄糖缺乏和 2-脱氧-D-葡萄糖（2DG）处理选择性地诱导了脾脏 CD205⁺ G-MDSCs 的大量死亡。有趣的是，2DG 模拟了 IF 选择性抑制脾脏中 CD205⁺ G-MDSCs 积累、上调肿瘤中裂解的半胱天冬酶 3、下调肺中 Ki67 以及延缓移植的 4T1 和 4T07 小鼠乳腺肿瘤生长的现象。这些发现表明，IF 通过下调 CXCR4 抑制细胞转运，并通过改变葡萄糖代谢诱导细胞凋亡；这抑制了肿瘤诱导的脾脏 CD205⁺ G-MDSCs 的积累，进而增强了抗肿瘤免疫力。
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