The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2.
The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2.
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DOI：
10.1016/j.molcel.2017.01.021
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发表时间：
2017-02-16
期刊：
影响因子：
16
通讯作者：
Walczak H
中科院分区：
文献类型：
--
作者：
Hartwig T;Montinaro A;von Karstedt S;Sevko A;Surinova S;Chakravarthy A;Taraborrelli L;Draber P;Lafont E;Arce Vargas F;El-Bahrawy MA;Quezada SA;Walczak H
已知肿瘤坏死因子（TNF）相关的肿瘤坏死诱导配体（TRAIL）特异性杀伤癌细胞，而在耐药癌症中，TRAIL/TRAIL-R可以通过Rac 1和PI 3 K促进转移。然而，癌细胞中的TRAIL/TRAIL-R信号传导是否以及在多大程度上可以影响免疫微环境仍然是未知的。在这里，我们表明，从TRAIL耐药癌细胞的TRAIL触发的细胞因子分泌是FADD依赖性的，并确定TRAIL诱导的分泌组驱动单核细胞极化骨髓源性抑制细胞（MDSC）和M2样巨噬细胞。肿瘤细胞中的TRAIL-R抑制损害了CCL 2的产生，并减少了肺MDSC的存在和肿瘤生长。因此，需要CCL 2的受体CCR 2来促进MDSC存在和肿瘤生长的增加。最后，在肺腺癌患者中，TRAIL和CCL 2与MDSC/M2标志物共调节。总的来说，内源性TRAIL/TRAIL-R介导的CCL 2分泌促进肿瘤支持性免疫细胞在癌症微环境中的积累，从而揭示了TRAIL/TRAIL-R系统在癌症生物学中的肿瘤支持性免疫调节作用。TRAIL以FADD-和半胱天冬酶-8-依赖性方式诱导细胞因子癌症分泌组FADD促进肿瘤生长沿着体内M2样免疫细胞的积累TRAIL诱导的分泌组通过CCR 2将M2样免疫细胞募集至肿瘤。显示癌细胞中的内源性TRAIL信号传导诱导FADD依赖性分泌组，其通过宿主CCR 2促进M2样免疫细胞的积累和肿瘤生长。
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for specifically killing cancer cells, whereas in resistant cancers, TRAIL/TRAIL-R can promote metastasis via Rac1 and PI3K. It remains unknown, however, whether and to what extent TRAIL/TRAIL-R signaling in cancer cells can affect the immune microenvironment. Here we show that TRAIL-triggered cytokine secretion from TRAIL-resistant cancer cells is FADD dependent and identify the TRAIL-induced secretome to drive monocyte polarization to myeloid-derived suppressor cells (MDSCs) and M2-like macrophages. TRAIL-R suppression in tumor cells impaired CCL2 production and diminished both lung MDSC presence and tumor growth. In accordance, the receptor of CCL2, CCR2, is required to facilitate increased MDSC presence and tumor growth. Finally, TRAIL and CCL2 are co-regulated with MDSC/M2 markers in lung adenocarcinoma patients. Collectively, endogenous TRAIL/TRAIL-R-mediated CCL2 secretion promotes accumulation of tumor-supportive immune cells in the cancer microenvironment, thereby revealing a tumor-supportive immune-modulatory role of the TRAIL/TRAIL-R system in cancer biology. TRAIL induces a cytokine cancer secretome in a FADD- and caspase-8-dependent manner FADD promotes tumor growth along with accumulation of M2-like immune cells in vivo The TRAIL-induced secretome recruits M2-like immune cells to tumors via CCR2 TRAIL/CCL2 correlate with a tumor-supportive immune profile in lung cancer patients Hartwig et al. show that endogenous TRAIL signaling in cancer cells induces a FADD-dependent secretome that promotes the accumulation of M2-like immune cells and tumor growth via host CCR2.