Colorectal cancer metastases in the liver establish immunosuppressive spatial networking between tumor associated SPP1+ macrophages and fibroblasts

Sathe A, Mason K, Grimes SM, Zhou Z, Lau BT, Bai X, Su A, Tan X, Lee H, Suarez CJ, Nguyen Q, Poultsides G, Zhang NR, Ji HP.

Clin Cancer Res.

October 14, 2022

Purpose: The liver is the most frequent metastatic site for colorectal cancer (CRC). Its microenvironment is modified to provide a niche that is conducive for CRC cell growth.This study focused on characterizing the cellular changes in the metastatic CRC (mCRC) liver tumor microenvironment (TME).

Experimental design: We analyzed a series of microsatellite stable (MSS) mCRCs to the liver, paired normal liver tissue and peripheral blood mononuclear cells using single cell RNA-seq (scRNA-seq). We validated our findings using multiplexed spatial imaging and bulk gene expression with cell deconvolution.

Results: We identified TME-specific SPP1-expressing macrophages with altered metabolism features, foam cell characteristics and increased activity in extracellular matrix (ECM) organization. SPP1+ macrophages and fibroblasts expressed complementary ligand receptor pairs with the potential to mutually influence their gene expression programs. TME lacked dysfunctional CD8 T cells and contained regulatory T cells, indicative of immunosuppression. Spatial imaging validated these cell states in the TME. Moreover, TME macrophages and fibroblasts had close spatial proximity, which is a requirement for intercellular communication and networking.In an independent cohort of mCRCs in the liver, we confirmed the presence of SPP1+ macrophages and fibroblasts using gene expression data. An increased proportion of TME fibroblasts was associated with a worst prognosis in these patients.

Conclusions: We demonstrated that mCRC in the liver is characterized by transcriptional alterations of macrophages in the TME. Intercellular networking between macrophages and fibroblasts supports CRC growth in the immunosuppressed metastatic niche in the liver. These features can be used to target immune checkpoint resistant MSS tumors.

Last updated: November 08, 2022