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, Noémi Kedei, Martin Arhin, Shadin Ghabra, Francisco Rodríguez-Matos, Mohamed-Reda Benmebarek, Chi Ma, Firouzeh Korangy, Tim F. Greten
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.