PO.IM02.05 · 免疫学
肿瘤干细胞重编程中性粒细胞以建立保护性生态位
Tumor stem cells reprogram neutrophils to establish a protective niche
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肿瘤相关中性粒细胞（TANs）的异质性已获认识，但TANs不同细胞状态如何产生、演化、分布并影响癌症免疫治疗疗效，仍不清楚。我们利用单细胞RNA测序、空间转录组学和遗传学操作，证明抗PDL1 + CD40激动剂免疫治疗可在TANs中诱导干扰素应答，使其在鳞状细胞癌（SCC）中重新获得抗肿瘤活性。相比之下，位于肿瘤-基质界面的TANs可保持其免疫抑制状态。重要的是，我们在肿瘤-基质界面鉴定出一群SOX2高表达的肿瘤起始干细胞（tSCs），它们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TANs中的前列腺素E2（PGE2）信号，从而破坏干扰素应答并阻止TANs中干扰素诱导的抗肿瘤功能。通过精细调控中性粒细胞的可塑性，tSCs塑造了中性粒细胞的异质性，并雕琢出一个保护性微生态位，以在免疫治疗中存活并驱动癌症复发。
查看英文原文 English abstract
The heterogeneous nature of tumor-associated neutrophils (TANs) has been recognized, but how different cell states of TANs emerge, evolve, distribute, and impact cancer immunotherapy efficacy remain elusive. Using single-cell RNA sequencing, spatial transcriptomics, and genetic manipulations, we show that anti-PDL1 + CD40 agonist immunotherapy can induce interferon responses in TANs, allowing them to regain antitumor activities in squamous cell carcinomas (SCC). In contrast, TANs residing at the tumor-stroma interface can preserve their immune suppressive state. Importantly, we identify a group of SOX2 High tumor-initiating stem cells (tSCs) at the tumor-stroma interface that upregulate fatty acid desaturase 1 (Fads1) to produce arachidonic acid (AA). This tSC-specific pathway enhances the prostaglandin E 2 (PGE 2 ) signaling in TANs, which can disrupt the interferon response and prevent the interferon-induced anti-tumor functions in TANs. By fine-tuning the plasticity of neutrophils, tSCs shape neutrophil heterogeneity and sculpt a protective micro-niche to survive from immunotherapy and drive cancer relapse.
利益披露 Disclosure
W. Guo, None.