SPP1 + macrophages cause exhaustion of tumor-specific T cells in liver metastases

Rajiv Trehan, Patrick Huang, Xiao Bin Zhu, Xin Wang, Marlaine Soliman, Dillon Strepay, Amran Nur, Noemi Kedei, Martin Arhin, Shadin Ghabra, Francisco Rodríguez-Matos, Mohamed-Reda Benmebarek, Chi Ma, Firouzeh Korangy and Tim F. Greten ()
Additional contact information
Rajiv Trehan: National Institutes of Health
Patrick Huang: National Institutes of Health
Xiao Bin Zhu: National Institutes of Health
Xin Wang: National Institutes of Health
Marlaine Soliman: National Institutes of Health
Dillon Strepay: National Institutes of Health
Amran Nur: National Institutes of Health
Noemi Kedei: National Institutes of Health
Martin Arhin: National Institutes of Health
Shadin Ghabra: National Institutes of Health
Francisco Rodríguez-Matos: National Institutes of Health
Mohamed-Reda Benmebarek: National Institutes of Health
Chi Ma: National Institutes of Health
Firouzeh Korangy: National Institutes of Health
Tim F. Greten: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-59529-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59529-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-59529-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().