Intermittent fasting suppressed splenic CD205+ G-MDSC accumulation in a murine breast cancer model by attenuating cell trafficking and inducing apoptosis.
Intermittent fasting suppressed splenic CD205+ G-MDSC accumulation in a murine breast cancer model by attenuating cell trafficking and inducing apoptosis.
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DOI：
10.1002/fsn3.2510
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发表时间：
2021-10
影响因子：
3.9
通讯作者：
Lyu S
中科院分区：
文献类型：
--
作者：
Fu C;Lu Y;Zhang Y;Yu M;Ma S;Lyu S
基于免疫的干预是新癌症治疗实现长期无癌生存的最有希望的方法。然而，髓源性抑制细胞（MDSC）的扩增削弱了免疫疗法的治疗潜力。我们最近发现，CD 205+粒细胞MDSC（G-MDSC），而不是T细胞，对葡萄糖缺乏敏感。间歇性禁食（IF）可以通过降低血糖水平来抑制恶性肿瘤细胞的生长，但关于IF对MDSC扩增的影响知之甚少。在本文中，我们观察到IF选择性地抑制4 T1和4 T07移植鼠乳腺癌模型中CD 205 + G-MDSC的脾脏积累。IF抑制肿瘤生长的效率与多西他赛相当。进一步检查显示，CXCR 4表达集中在肿瘤诱导的G-MDSC的CD 205+亚群中。CXCR 4的下调与IF治疗下从骨髓到脾脏的CD 205 + G-MDSC运输的减少相关。此外，离体培养测定显示葡萄糖缺乏和2-脱氧-D-葡萄糖（2DG）处理选择性地诱导脾CD 205 + G-MDSC的大量死亡。有趣的是，2DG模拟了IF选择性抑制脾脏中CD 205 + G-MDSC的积累，上调肿瘤中切割的半胱天冬酶3，下调肺中的Ki 67，并延缓移植的4 T1和4 T07小鼠乳腺肿瘤的生长的现象。这些发现表明，IF通过下调CXCR 4抑制细胞运输，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CD 205 + G-MDSC的积累，进而增强了抗肿瘤免疫力。我们观察到，间歇性禁食不仅限制了乳腺肿瘤的生长，还抑制了免疫抑制细胞的积累，这表明间歇性禁食有可能增强癌症宿主的免疫系统，是提高癌症免疫治疗有效性的辅助治疗选择。
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. We observed that intermittent fasting not only limits the growth of breast tumors but also inhibits the accumulation of immunosuppressive cells, suggesting that intermittent fasting has the potential to enhance the immune system of cancer hosts and is an adjuvant treatment option to improve the effectiveness of cancer immunotherapy.
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影响因子：
50.3
作者：
Di Biase S;Lee C;Brandhorst S;Manes B;Buono R;Cheng CW;Cacciottolo M;Martin-Montalvo A;de Cabo R;Wei M;Morgan TE;Longo VD
通讯作者：
Longo VD
影响因子：
7.3
作者：
Fleming V;Hu X;Weber R;Nagibin V;Groth C;Altevogt P;Utikal J;Umansky V
通讯作者：
Umansky V
影响因子：
17.1
作者：
Highfill SL;Cui Y;Giles AJ;Smith JP;Zhang H;Morse E;Kaplan RN;Mackall CL
通讯作者：
Mackall CL
影响因子：
29
作者：
Brandhorst S;Choi IY;Wei M;Cheng CW;Sedrakyan S;Navarrete G;Dubeau L;Yap LP;Park R;Vinciguerra M;Di Biase S;Mirzaei H;Mirisola MG;Childress P;Ji L;Groshen S;Penna F;Odetti P;Perin L;Conti PS;Ikeno Y;Kennedy BK;Cohen P;Morgan TE;Dorff TB;Longo VD
通讯作者：
Longo VD
影响因子：
15.9
作者：
Eash, Kyle J.;Greenbaum, Adam M.;Link, Daniel C.
通讯作者：
Link, Daniel C.