Division of Hematology and Oncology, Department of Medicine, New Jersey Medical School, Newark, NJ 07103, USA.
J Immunol. 2010 May 15;184(10):5885-94. doi: 10.4049/jimmunol.0903143. Epub 2010 Apr 9.
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(reg) levels after coculture with MSCs and found an approximately 2-fold increase in T(regs), with associated decreases in antitumor Th1 cytokines and increases in Th2 cytokines. MSC-derived TGF-beta1 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-beta1. 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.
间充质干细胞 (MSCs) 已被证明可促进乳腺癌生长。由于 MSCs 还增加了调节性 T 细胞 (Tregs) 的频率，因此本研究检验了这样一个假设，即人 MSCs 通过 Tregs 保护乳腺癌细胞 (BCCs) 免受免疫清除。MSCs 抑制 PBMC 增殖，当后者暴露于 γ 射线照射的 BCCs 时。同样，MSCs 对 PBMC 向 BCCs 的迁移表现出显著的抑制作用，并且相应地降低了 CXCL12。MSCs 还抑制 NK 细胞和 CTL 功能，与平行培养物相比，MSCs 减少了 CD8(+)和 CD56(+)细胞的数量。减少的 NK 和 CTL 活性与细胞内和分泌的 granzyme B 减少相关。为了解释这些免疫抑制发现，我们比较了与 MSCs 共培养后 Treg 的水平，发现 Treg 增加了约 2 倍，同时抗肿瘤 Th1 细胞因子减少，Th2 细胞因子增加。基于敲低研究，MSC 衍生的 TGF-β1 是 Treg 增加的主要原因。在 Treg 耗尽的情况下，PBMC 增殖和效应功能部分恢复。总之，这些研究表明，在 PBMC 和 BCC 共培养物中，MSC 介导了 Treg 的增加。结果部分可以通过 Th2 型细胞因子和 MSC 产生的 TGF-β1 的增加来解释。这些发现表明 MSCs 对 BCC 具有免疫保护作用。MSCs 介导的免疫细胞增殖和募集减少对乳腺癌的化疗治疗具有重要意义。
