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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月7日

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  • 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,
  • Tim F. Greten

摘要

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.