Orchestration of myeloid-derived suppressor cells in the tumor microenvironment by ubiquitous cellular protein TCTP released by tumor cells
Orchestration of myeloid-derived suppressor cells in the tumor microenvironment by ubiquitous cellular protein TCTP released by tumor cells
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DOI：
10.1038/s41590-021-00967-5
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发表时间：
2021-07-08
影响因子：
30.5
通讯作者：
Taniguchi, Tadatsugu
中科院分区：
文献类型：
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作者：
Hangai, Sho;Kawamura, Takeshi;Taniguchi, Tadatsugu
在癌症治疗的背景下，细胞死亡通常与免疫原性有关。Taniguchi和他的同事发现，细胞死亡后细胞蛋白TCTP的释放触发了肿瘤微环境中的免疫抑制途径。肿瘤免疫学中最具挑战性的问题之一是更好地理解骨髓源性抑制细胞（MDSCs）在肿瘤微环境（TIME）中积累的动力学，因为这将导致新的癌症治疗方法的发展。在这里，我们发现垂死的肿瘤细胞释放的翻译控制肿瘤蛋白（TCTP）是一种免疫调节剂，对成熟的MDSC积累至关重要。我们提供的证据表明，细胞外TCTP通过激活toll样受体-2介导多形核MDSC （PMN-MDSC）群体在TIME中的募集。作为进一步的原理证明，我们发现抑制TCTP可以抑制PMN-MDSC的积累和肿瘤的生长。在人类癌症中，我们发现TCTP的升高和TCTP基因剂量与抗肿瘤免疫特征和临床预后呈负相关。本研究揭示了迄今为止知之甚少的MDSC在TIME中的动力学机制，为癌症免疫治疗提供了新的理论基础。
Cell death in the context of cancer therapies is often associated with immunogenicity. Taniguchi and colleagues instead find that release of the cellular protein TCTP following cell death triggers an immunosuppressive pathway in the tumor microenvironment.One of most challenging issues in tumor immunology is a better understanding of the dynamics in the accumulation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TIME), as this would lead to the development of new cancer therapeutics. Here, we show that translationally controlled tumor protein (TCTP) released by dying tumor cells is an immunomodulator crucial to full-blown MDSC accumulation in the TIME. We provide evidence that extracellular TCTP mediates recruitment of the polymorphonuclear MDSC (PMN-MDSC) population in the TIME via activation of Toll-like receptor-2. As further proof of principle, we show that inhibition of TCTP suppresses PMN-MDSC accumulation and tumor growth. In human cancers, we find an elevation of TCTP and an inverse correlation of TCTP gene dosage with antitumor immune signatures and clinical prognosis. This study reveals the hitherto poorly understood mechanism of the MDSC dynamics in the TIME, offering a new rationale for cancer immunotherapy.