Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β
Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β
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DOI：
10.4049/jimmunol.0903143
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发表时间：
2010-05-15
影响因子：
4.4
通讯作者：
Rameshwar, Pranela
中科院分区：
文献类型：
--
作者：
Patel, Shyam A.;Meyer, Justin R.;Rameshwar, Pranela
间充质干细胞（MSCs）已被证明可促进乳腺癌生长。由于MSCs还会增加调节性T细胞（Tregs）的频率，本研究验证了人类MSCs通过Tregs保护乳腺癌细胞（BCCs）免受免疫清除这一假设。当外周血单个核细胞（PBMCs）暴露于经γ射线照射的BCCs时，MSCs会抑制PBMCs的增殖。同样，MSCs对PBMCs向BCCs的迁移有显著抑制作用，并且CXCL12相应减少。MSCs还抑制自然杀伤（NK）细胞和细胞毒性T淋巴细胞（CTL）的功能，与不含MSCs的平行培养相比，CD8(+)和CD56(+)细胞数量减少。NK和CTL活性的降低与细胞内和分泌的颗粒酶B减少相关。为了解释这些免疫抑制的发现，我们比较了与MSCs共培养后的Tregs水平，发现Tregs增加了约2倍，同时抗肿瘤的Th1细胞因子减少，Th2细胞因子增加。基于基因敲低研究，MSCs衍生的转化生长因子 - β1（TGF - 1β）在很大程度上导致了Tregs的增加。在Tregs耗竭的情况下，PBMCs的增殖和效应功能部分恢复。总之，这些研究表明在PBMCs和BCCs共培养中MSCs介导了Tregs的增加。这些结果可以部分地由Th2型细胞因子的增加和MSCs产生的TGF - 1β来解释。这些发现证明了MSCs对BCCs的免疫保护作用。MSCs介导的免疫细胞增殖和募集的减少对乳腺癌的化疗治疗具有影响。《免疫学杂志》，2010年，184卷：5885 - 5894页。
Mesenchymal stem cells (MSCs) have been shown to support breast cancer growth. Because MSCs also increase the frequency of regulatory T cells (T-regs), this study tested the hypothesis that human MSCs, via Tregs, protect breast cancer cells (BCCs) from immune clearance MSCs suppressed the proliferation of PBMCs when the latter were exposed to gamma-irradiated BCCs. Similarly, MSCs showed significant inhibition of PBMC migration toward BCCs and a corresponding decrease in CXCL12. MSCs also inhibited NK cell and CTL functions, which correlated with reduced numbers of CD8(+) and CD56(+) cells compared with parallel cultures without MSCs. The reduced NK and CTL activities correlated with a decrease in intracellular and secreted granzyme B. To explain these immunosuppressive findings, we compared T-regs levels after coculture with MSCs and found an similar to 2-fold increase in T-regs, with associated decreases in antitumor Th1 cytokines and increases in Th2 cytokines. MSC-derived TGF-1 beta was largely responsible for the increase in T-regs based on knockdown studies. In the presence of T-reg depletion, PBMC proliferation and effector functions were partially restored. Together, these studies show an MSC-mediated increase in T-regs in cocultures of PBMCs and BCCs. The results could be explained, in part, by the increase in Th2-type cytokines and MSC-generated TGF-1 beta. These findings demonstrate immune protection by MSCs to BCCs. The reduction in immune cell proliferation and recruitment mediated by MSCs has implications for treatment of breast cancer with chemotherapy. The Journal of Immunology, 2010, 184: 5885-5894.