Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
J Clin Invest. 2012 Nov;122(11):4094-104. doi: 10.1172/JCI64115. Epub 2012 Oct 15.
TNF, an inflammatory cytokine that is enriched in the tumor microenvironment, promotes tumor growth and subverts innate immune responses to cancer cells. We previously reported that tumors implanted in TNF receptor-deficient (Tnfr-/-) mice are spontaneously rejected; however, the molecular mechanisms underlying this rejection are unclear. Here we report that TNF signaling drives the peripheral accumulation of myeloid-derived suppressor cells (MDSCs). MDSCs expand extensively during inflammation and tumor progression in mice and humans and can enhance tumor growth by repressing T cell-mediated antitumor responses. Peripheral accumulation of MDSCs was drastically impaired in Tnfr-/- mice. Signaling of TNFR-2, but not TNFR-1, promoted MDSC survival through upregulation of cellular FLICE-inhibitory protein (c-FLIP) and inhibition of caspase-8 activity. Loss of TNFRs impaired the induction of MDSCs from bone marrow cells, but this could be reversed by treatment with caspase inhibitors. These results demonstrate that TNFR-2 signaling promotes MDSC survival and accumulation and helps tumor cells evade the immune system.
肿瘤坏死因子（TNF）是一种在肿瘤微环境中富集的炎症细胞因子，它促进肿瘤生长并颠覆了对癌细胞的固有免疫反应。我们之前曾报道过，植入 TNF 受体缺陷（Tnfr-/-）小鼠体内的肿瘤会自发排斥；然而，这种排斥的分子机制尚不清楚。在这里，我们报告称 TNF 信号通路驱动髓系来源的抑制细胞（MDSC）在外周的积累。MDSC 在小鼠和人类的炎症和肿瘤进展过程中广泛扩增，可通过抑制 T 细胞介导的抗肿瘤反应来促进肿瘤生长。Tnfr-/- 小鼠中 MDSC 的外周积累明显受损。TNFR-2 的信号传导而不是 TNFR-1 的信号传导，通过上调细胞 FLICE 抑制蛋白（c-FLIP）和抑制半胱天冬酶-8 活性来促进 MDSC 的存活。TNFRs 的缺失会损害骨髓细胞中 MDSC 的诱导，但通过使用半胱天冬酶抑制剂处理可以逆转这种情况。这些结果表明，TNFR-2 信号通路促进了 MDSC 的存活和积累，帮助肿瘤细胞逃避免疫系统。
