Emilien J. Loeuillard , Binbin Li , Hannah E. Stumpf , Jingchun Yang , Jessica R. Willhite , Jennifer L. Tomlinson , Fred Rakhshan Rohakhtar , Vernadette A. Simon , Rondell P. Graham , Rory L. Smoot , Haidong Dong , Sumera I. Ilyas
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Herein, we aimed to define mechanisms by which TRAIL<sup>+</sup> cancer cells can leverage noncanonical TRAIL signaling in myeloid-derived suppressor cells (MDSCs) promoting their abundance in murine cholangiocarcinoma (CCA).</p></div><div><h3>Methods</h3><p>Multiple immunocompetent syngeneic, orthotopic models of CCA were used. Single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing of CD45<sup>+</sup> cells in murine tumors from the different CCA models was conducted.</p></div><div><h3>Results</h3><p>In multiple immunocompetent murine models of CCA, implantation of TRAIL<sup>+</sup> murine cancer cells into <em>Trail-r</em><sup><em>-/-</em></sup> mice resulted in a significant reduction in tumor volumes compared with wild-type mice. Tumor-bearing <em>Trail-r</em><sup><em>-/-</em></sup> mice had a significant decrease in the abundance of MDSCs owing to attenuation of MDSC proliferation. Noncanonical TRAIL signaling with consequent nuclear factor-κB activation in MDSCs facilitated enhanced MDSC proliferation. Single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing of immune cells from murine tumors showed enrichment of a nuclear factor-κB activation signature in MDSCs. Moreover, MDSCs were resistant to TRAIL-mediated apoptosis owing to enhanced expression of cellular FLICE inhibitory protein, an inhibitor of proapoptotic TRAIL signaling. Accordingly, cellular FLICE inhibitory protein knockdown sensitized murine MDSCs to TRAIL-mediated apoptosis. 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引用次数: 0
摘要
背景与目的：促凋亡的肿瘤坏死因子相关凋亡诱导配体（TRAIL）信号是导致癌细胞死亡的一个公认机制。然而，TRAIL-受体（TRAIL-R）激动剂在人体中的抗癌活性非常有限，这对TRAIL作为一种强效抗癌剂的概念提出了挑战。在此，我们旨在确定TRAIL+癌细胞可利用髓源性抑制细胞（MDSCs）中的非典型TRAIL信号促进其在小鼠胆管癌（CCA）中大量存在的机制：方法：使用多种免疫功能正常的 CCA 正位模型。方法：采用多种免疫能力强的同种异体小鼠模型，对不同 CCA 模型小鼠肿瘤中的 CD45+ 细胞进行单细胞 RNA 测序（scRNA-seq）和转录组细胞索引及表位测序（CITE-seq）：结果：在多种免疫功能正常的 CCA 小鼠模型中，与野生型小鼠相比，将 TRAIL+ 小鼠癌细胞植入 Trail-r-/- 小鼠体内可显著减少肿瘤体积。由于MDSC增殖减弱，肿瘤携带Trail-r-/-小鼠的MDSC数量显著减少。小鼠肿瘤免疫细胞的 scRNA-seq 和 CITE-seq 结果表明，MDSCs 中 NF-κB 激活特征丰富。此外，由于细胞FLICE抑制蛋白（cFLIP）表达增强，MDSCs对TRAIL介导的细胞凋亡具有抵抗力。因此，敲除 cFLIP 可使小鼠 MDSCs 对 TRAIL 介导的细胞凋亡敏感。最后，癌细胞限制性缺失Trail可显著降低MDSC丰度和小鼠肿瘤负荷：我们的研究结果凸显了靶向TRAIL+癌细胞治疗免疫原性低的癌症的治疗潜力。
Noncanonical TRAIL Signaling Promotes Myeloid-Derived Suppressor Cell Abundance and Tumor Growth in Cholangiocarcinoma
Background & Aims
Proapoptotic tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) signaling as a cause of cancer cell death is a well-established mechanism. However, TRAIL-receptor (TRAIL-R) agonists have had very limited anticancer activity in human beings, challenging the concept of TRAIL as a potent anticancer agent. Herein, we aimed to define mechanisms by which TRAIL+ cancer cells can leverage noncanonical TRAIL signaling in myeloid-derived suppressor cells (MDSCs) promoting their abundance in murine cholangiocarcinoma (CCA).
Methods
Multiple immunocompetent syngeneic, orthotopic models of CCA were used. Single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing of CD45+ cells in murine tumors from the different CCA models was conducted.
Results
In multiple immunocompetent murine models of CCA, implantation of TRAIL+ murine cancer cells into Trail-r-/- mice resulted in a significant reduction in tumor volumes compared with wild-type mice. Tumor-bearing Trail-r-/- mice had a significant decrease in the abundance of MDSCs owing to attenuation of MDSC proliferation. Noncanonical TRAIL signaling with consequent nuclear factor-κB activation in MDSCs facilitated enhanced MDSC proliferation. Single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing of immune cells from murine tumors showed enrichment of a nuclear factor-κB activation signature in MDSCs. Moreover, MDSCs were resistant to TRAIL-mediated apoptosis owing to enhanced expression of cellular FLICE inhibitory protein, an inhibitor of proapoptotic TRAIL signaling. Accordingly, cellular FLICE inhibitory protein knockdown sensitized murine MDSCs to TRAIL-mediated apoptosis. Finally, cancer cell–restricted deletion of Trail significantly reduced MDSC abundance and murine tumor burden.
Conclusions
Our findings highlight the therapeutic potential of targeting TRAIL+ cancer cells for treatment of a poorly immunogenic cancer.
期刊介绍：
"Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology.
CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.
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