SPP1 + macrophages cause exhaustion of tumor-specific T cells in liver metastases
Functional tumor-specific CD8+ T cells are essential for effective anti-tumor immune response and immune checkpoint inhibitor therapy. Here we show that, compared to other organ sites, primary, metastatic liver tumors in murine models contain a higher number of tumor-specific CD8+ T cells which are also dysfunctional. High-dimensional, multi-omic analysis of patient samples reveals a higher frequency of exhausted tumor-reactive CD8+ T cells and enriched interactions between these cells and SPP1+ macrophages in profibrotic, alpha-SMA rich regions specifically in the liver. Differential pseudotime trajectory inference analysis reveals that extrahepatic signaling promotes an intermediate cell (IC) population in the liver, characterized by co-expression of VISG4, CSF1R, CD163, TGF-βR, IL-6R, and SPP1. Analysis of premetastatic adenocarcinoma patient samples reveals enrichment of this population may predict liver metastasis. These findings suggest a mechanism by which extrahepatic tumors drive liver metastasis by promoting an IC population that inhibits tumor-reactive CD8+ T cell function.
Authors
- Dillon Strepay (ORCID: https://orcid.org/0000-0003-2120-4857)
- Martin Arhin (ORCID: https://orcid.org/0000-0002-1266-3659)
- Firouzeh Korangy (ORCID: https://orcid.org/0000-0002-0712-1409)
- Francisco Rodríguez-Matos (ORCID: https://orcid.org/0000-0002-8469-477X)
- Xin Wang (ORCID: https://orcid.org/0000-0002-6105-1149)
- Patrick Huang (ORCID: https://orcid.org/0000-0003-4833-8134)
- Amran Nur (ORCID: https://orcid.org/0000-0002-9890-1004)
- Rajiv Trehan (ORCID: https://orcid.org/0000-0002-2819-0534)
- Noémi Kedei (ORCID: https://orcid.org/0000-0002-6625-6119)
- Shadin Ghabra (ORCID: https://orcid.org/0000-0002-1505-2992)
- Tim F. Greten (ORCID: https://orcid.org/0000-0002-0806-2535)
- Xiao Bin Zhu
- Chi Ma (ORCID: https://orcid.org/0000-0002-4171-0813)
- Mohamed-Reda Benmebarek (ORCID: https://orcid.org/0000-0002-1201-7067)
- Marlaine Soliman
Institutions
- National Institutes of Health (US)
- Office of the Director (US)
- National Institute of Neurological Disorders and Stroke (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- National Institute on Deafness and Other Communication Disorders (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-07
- DOI
- https://doi.org/10.1038/s41467-025-59529-0
- Citations
- 31
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 24.72
Funders
- Colgate-Palmolive Company
- American Association for Dental, Oral, and Craniofacial Research
- National Institutes of Health
- National Cancer Institute