Yofe Ido, Shami Tamar, Cohen Noam, Landsberger Tomer, Sheban Fadi, Stoler-Barak Liat, Yalin Adam, Phan Truong San, Li Baoguo, Monteran Lea, Scharff Ye'ela, Giladi Amir, Elbaz Miriam, David Eyal, Gurevich-Shapiro Anna, Gur Chamutal, Shulman Ziv, Erez Neta, Amit Ido
Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Cancer Discov. 2023 Dec 12;13(12):2610-2631. doi: 10.1158/2159-8290.CD-23-0299.
Cancer mortality primarily stems from metastatic recurrence, emphasizing the urgent need for developing effective metastasis-targeted immunotherapies. To better understand the cellular and molecular events shaping metastatic niches, we used a spontaneous breast cancer lung metastasis model to create a single-cell atlas spanning different metastatic stages and regions. We found that premetastatic lungs are infiltrated by inflammatory neutrophils and monocytes, followed by the accumulation of suppressive macrophages with the emergence of metastases. Spatial profiling revealed that metastasis-associated immune cells were present in the metastasis core, with the exception of TREM2+ regulatory macrophages uniquely enriched at the metastatic invasive margin, consistent across both murine models and human patient samples. These regulatory macrophages (Mreg) contribute to the formation of an immune-suppressive niche, cloaking tumor cells from immune surveillance. Our study provides a compendium of immune cell dynamics across metastatic stages and niches, informing the development of metastasis-targeting immunotherapies.
Temporal and spatial single-cell analysis of metastasis stages revealed new players in modulating immune surveillance and suppression. Our study highlights distinct populations of TREM2 macrophages as modulators of the microenvironment in metastasis, and as the key immune determinant defining metastatic niches, pointing to myeloid checkpoints to improve therapeutic strategies. This article is featured in Selected Articles from This Issue, p. 2489.
癌症死亡率主要源于转移性复发，这凸显了开发有效的靶向转移的免疫疗法的迫切需求。为了更好地理解塑造转移小生境的细胞和分子事件，我们使用了一个自发性乳腺癌肺转移模型来创建一个跨越不同转移阶段和区域的单细胞图谱。我们发现，转移前的肺部被炎性中性粒细胞和单核细胞浸润，随后随着转移灶的出现，抑制性巨噬细胞开始积累。空间分析显示，除了在转移侵袭边缘独特富集的TREM2 +调节性巨噬细胞外，转移相关免疫细胞存在于转移核心，在小鼠模型和人类患者样本中均一致。这些调节性巨噬细胞（Mreg）有助于形成免疫抑制小生境，使肿瘤细胞免受免疫监视。我们的研究提供了一份跨转移阶段和小生境的免疫细胞动态概要，为靶向转移的免疫疗法的开发提供了信息。
对转移阶段的时空单细胞分析揭示了调节免疫监视和抑制的新参与者。我们的研究强调了不同群体的TREM2巨噬细胞作为转移微环境的调节因子，以及作为定义转移小生境的关键免疫决定因素，指出了髓系检查点以改善治疗策略。本文发表于本期精选文章，第2489页。
