Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medicial University, Shanghai, China.
J Cell Mol Med. 2011 Nov;15(11):2343-52. doi: 10.1111/j.1582-4934.2010.01215.x.
Mesenchymal stem cells (MSCs) are studied for their potential clinical use in regenerative medicine, tissue engineering and tumour therapy. However, the therapeutic application of MSCs in tumour therapy still remains limited unless the immunosuppressive role of MSCs for tumour growth in vivo is better understood. In this study, we investigated the mechanism of MSCs favouring tumour escape from immunologic surveillance in inflammatory microenvironment. We first compared the promotive capacity of bone marrow-derived MSCs on B16 melanoma cells growth in vivo, pre-incubated or not with the inflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF)-α. We showed that the development of B16 melanoma cells is faster when co-injected with MSCs pre-incubated with IFN-γ and TNF-α compared with control groups. Moreover, tumour incidence increases obviously in allogeneic recipients when B16 melanoma cells were co-injected with MSCs pre-incubated with IFN-γ and TNF-α. We then demonstrated that the immunosuppressive function of MSCs was elicited by IFN-γ and TNF-α. These cytokine combinations provoke the expression of inducible nitric oxide synthase (iNOS) by MSCs. The impulsive effect of MSCs treated with inflammatory cytokines on B16 melanoma cells in vivo can be reversed by inhibitor or short interfering RNA of iNOS. Our results suggest that the MSCs in tumour inflammatory microenvironment may be elicited of immunosuppressive function, which will help tumour to escape from the immunity surveillance.
间充质干细胞（MSCs）因其在再生医学、组织工程和肿瘤治疗中的潜在临床应用而受到研究。然而，除非更好地了解 MSCs 在体内对肿瘤生长的免疫抑制作用，否则 MSCs 在肿瘤治疗中的治疗应用仍然有限。在这项研究中，我们研究了 MSCs 在炎症微环境中有利于肿瘤逃避免疫监视的机制。我们首先比较了骨髓来源的 MSCs 在体内对 B16 黑色素瘤细胞生长的促进能力，这些 MSCs 预先用炎症细胞因子干扰素（IFN）-γ和肿瘤坏死因子（TNF）-α孵育或未孵育。结果表明，与对照组相比，与预先用 IFN-γ和 TNF-α孵育的 MSCs 共注射时，B16 黑色素瘤细胞的发育更快。此外，当与预先用 IFN-γ和 TNF-α孵育的 MSCs 共注射 B16 黑色素瘤细胞时，同种异体受体中的肿瘤发生率明显增加。然后，我们证明了 MSCs 的免疫抑制功能是由 IFN-γ 和 TNF-α引起的。这些细胞因子组合可诱导 MSCs 表达诱导型一氧化氮合酶（iNOS）。用炎症细胞因子处理的 MSCs 对体内 B16 黑色素瘤细胞的冲动作用可通过 iNOS 的抑制剂或短发夹 RNA 逆转。我们的结果表明，肿瘤炎症微环境中的 MSCs 可能被诱导出免疫抑制功能，这将有助于肿瘤逃避免疫监视。
