Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis.
Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis.
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DOI：
10.1038/ncomms11762
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发表时间：
2016-06-08
影响因子：
16.6
通讯作者：
Stewart SA
中科院分区：
文献类型：
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作者：
Ruhland MK;Loza AJ;Capietto AH;Luo X;Knolhoff BL;Flanagan KC;Belt BA;Alspach E;Leahy K;Luo J;Schaffer A;Edwards JR;Longmore G;Faccio R;DeNardo DG;Stewart SA
年龄是癌症发展的一个重要风险因素。然而，导致年龄相关癌症增加的机制仍然知之甚少。为了确定衰老的基质细胞是否影响肿瘤发生，我们开发了一种模拟衰老皮肤微环境的小鼠模型。使用这个模型，我们发现衰老的基质细胞足以驱动抑制性骨髓细胞的局部增加，这些细胞有助于肿瘤的促进。此外，我们发现基质来源的衰老相关分泌表型因子白细胞介素-6协调抑制性骨髓细胞及其抑制抗肿瘤T细胞应答的能力的增加。值得注意的是，在老年无癌个体中，我们发现免疫细胞也在衰老基质细胞附近出现类似的增加。这项工作提供的证据表明，衰老基质细胞的积累足以建立一个肿瘤允许的慢性炎症微环境，可以庇护初期肿瘤细胞，从而使它们能够在免疫系统的作用下增殖和发展。 患癌症的风险随着年龄的增长而增加。在这里，作者讨论了肿瘤间质隔室中衰老细胞的年龄依赖性积累的贡献，并表明衰老细胞增加了抑制细胞毒性T细胞的骨髓源性抑制细胞的浸润，从而促进肿瘤生长。
Age is a significant risk factor for the development of cancer. However, the mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells influence tumorigenesis, we develop a mouse model that mimics the aged skin microenvironment. Using this model, here we find that senescent stromal cells are sufficient to drive localized increases in suppressive myeloid cells that contributed to tumour promotion. Further, we find that the stromal-derived senescence-associated secretory phenotype factor interleukin-6 orchestrates both increases in suppressive myeloid cells and their ability to inhibit anti-tumour T-cell responses. Significantly, in aged, cancer-free individuals, we find similar increases in immune cells that also localize near senescent stromal cells. This work provides evidence that the accumulation of senescent stromal cells is sufficient to establish a tumour-permissive, chronic inflammatory microenvironment that can shelter incipient tumour cells, thus allowing them to proliferate and progress unabated by the immune system. The risk of developing cancer increases with age. Here, the authors address the contribution of age-dependent accumulation of senescent cells within the tumour stroma compartment and show that senescent cells increase the infiltration of myeloid-derived suppressor cells that inhibit cytotoxic T-cells, thus facilitating tumour outgrowth.