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Cited by 130Immune cells in cancerCancer Immunotherapy and BiomarkersCancer Cells and Metastasis

Spatial and Temporal Mapping of Breast Cancer Lung Metastases Identify TREM2 Macrophages as Regulators of the Metastatic Boundary

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Yofe, Ido, Shami, Tamar, Cohen, Noam, Landsberger, Tomer, Sheban, Fadi, Stoler-Barak, Liat, Yalin, Adam, Phan, Truong San +11 more·2023·Cancer Discovery
DOI 10.1158/2159-8290.cd-23-0299PMC PMC7617931

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Abstract

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. Significance: 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

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  • The LAM phenotype is not unique to the fibrotic liver, also being identified in other tissues in the context of sterile injury as well as in macrophages surrounding the bile duct in the healthy liver.

    “Interestingly, this phenotype is not unique to the fibrotic liver, also being identified in other tissues in the context of sterile injury (32, 33, 38, 110–121) as well as in macrophages surrounding the bile duct in the healthy liver (62).”

    From Targeting macrophages in liver fibrosis (2026) · cites this paper as [114]

    The Results section on the metastatic invasive margin reports TREM2+ macrophages with lipid-metabolism features in lung metastases and notes a similar macrophage population reported in pulmonary fibrosis. This supports the phenotype’s presence beyond fibrotic liver, but this paper’s own study concerns cancer metastases, not sterile injury; the healthy-liver bile-duct clause is attributed to a different citation. (LLM, conf=0.82)

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Cited by

Sorted by citations

Authors
Yofe, I., Shami, T., Cohen, N., Landsberger, T., Sheban, F., Stoler-Barak, L., Yalin, A., Phan, T. S., Li, B., Monteran, L., Scharff, Y., Giladi, A., Elbaz, M., David, E., Gurevich-Shapiro, A., Gur, C., Shulman, Z., Erez, N., & Amit, I.
Affiliations
  • Weizmann Institute of Science (IL)
  • Tel Aviv University (IL)
  • 1Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
Corresponding author
  • Yofe, Ido
  • Erez, Neta
  • Amit, Ido
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2023-09-27
Volume
13
Issue
12
Pages
2610-2631
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-23-0299
PMC
PMC7617931
OpenAlex
W4387088536
Cited by
130
References
13
Citations by year
2026: 47 · 2025: 47 · 2024: 34 · 2023: 2
FWCI
14.58
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by)
Funders
  • U.S. Department of Defense (W81XWH2110394)
  • HORIZON EUROPE European Research Council (101055341-TROJAN-Cell)
  • Israel Science Foundation (1090/18, #3495/19)
  • Israel Cancer Research Fund
  • Worldwide Cancer Research
  • Emerson Collective
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
breast cancer lung metastasis, TREM2+ macrophages, regulatory macrophages, metastatic niche, pre-metastatic niche, immune cell dynamics, immunosuppression, neutrophils, monocytes, single-cell atlas
MeSH terms
Animals, Breast Neoplasms, Female, Humans, Lung, Lung Neoplasms, Macrophages, Membrane Glycoproteins, Neoplasm Metastasis, Receptors, Immunologic, Mice, Tumor Microenvironment

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