LBPO.TB02 · 肿瘤生物学 · Late-Breaking
剖析塑造免疫抑制性肿瘤微环境的干性相关分子环路
Dissecting stemness associated molecular circuits that shape the immune suppressive tumor microenvironment
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摘要 Abstract
中文摘要
免疫逃逸是癌症的一个标志，但是否每个肿瘤细胞都采用相似的机制来逃避免疫监视仍存在争议。近期研究指出，富含干性相关基因特征的一部分癌细胞能够激活独特的免疫调节程序，使这些肿瘤起始干细胞（tSCs）能够更好地逃避或抵抗抗肿瘤免疫。然而，编排其特化免疫豁免程序的tSC特异性分子环路仍未明确。在此，我们比较了从不同组织来源的鳞状细胞癌（SCCs）中分离出的各种肿瘤细胞群的转录组。这一全面的分析界定了tSCs独特的免疫逃逸特性。将该分析与染色质景观图谱、遗传扰动和单细胞RNA测序相结合，我们发现TIC特异性免疫调节程序广泛受SOX2（一种干性相关转录因子）的调控。深入探究机制，我们首先发现SOX2上调脂肪酸去饱和酶1（Fads1）以产生花生四烯酸（AA）。这一tSC特异性通路增强了肿瘤相关中性粒细胞（TANs）中的前列腺素E2（PGE2）信号，可破坏干扰素反应并阻止TANs中干扰素诱导的抗肿瘤功能。此外，SOX2还促进tSCs产生CSF3，促使未成熟的TANs分泌CSF1，支持CD206+肿瘤相关巨噬细胞（TAMs）的发育。这种由SOX2编排的tSCs-TAN-TAM串扰随后塑造了一个局部免疫抑制龛，保护tSCs。本研究揭示SOX2作为主调控因子，掌控保守的干性相关免疫调节环路，赋予tSCs增强的能力以维持髓系细胞的促肿瘤和免疫抑制细胞状态。这些发现将tSCs置于顶端位置，在此它们指导免疫抑制性肿瘤微环境的组织构建。
查看英文原文 English abstract
Immune evasion is a hall mark of cancer, but whether every tumor cell employs similar mechanisms to escape immune surveillance is still under debate. Recent studies pointed to a subset of cancer cells that are enriched with stemness related gene signatures can activate unique immune modulatory program, allowing these tumor initiating stem cells (tSCs) to better evade or resist anti-tumor immunity. However, the tSC specific molecular circuit that orchestrate their specialized immune privilege program remains undefined. Here, we compared the transcriptome of various tumor cell populations isolated from squamous cell carcinomas (SCCs) derived from different tissues. This comprehensive profiling defined distinct immune evasive properties of tSCs. Combining this analysis with chromatin landscape mapping, genetic perturbation, and single cell RNA-sequencing, we identified that the TIC-specific immune modulatory program is broadly regulated by SOX2, a stemness-associated transcription factor. Delving into the mechanism, we first found that SOX2 upregulates fatty acid desaturase 1 (Fads1) to produce arachidonic acid (AA). This tSC specific pathway enhances the prostaglandin E2 (PGE2) signaling in tumor-associated neutrophils (TANs), which can disrupt the interferon response and prevent the interferon induced anti tumor functions in TANs. In addition, SOX2 also promotes tSCs to produce CSF3, facilitating the immature TANs to secrete CSF1, supporting the development of CD206+ tumor-associated macrophages (TAMs). This tSCs TAN TAM crosstalk orchestrated by SOX2 then sculpts a localized immune suppressive niche that protect tSCs. This study uncovers SOX2 functions as the master regulator that governs the conserved stemness-associated immune modulatory circuits to endow the tSCs with enhanced ability to sustain the pro-tumor and immune suppressive cell states of myeloid cells. These findings placed tSCs at the apex position where they instruct the organization of the immune suppressive tumor microenvironment.
利益披露 Disclosure
Y. Miao, None.