journal contribution
posted on 2023-04-01, 00:01 authored by Anuja Sathe, Kaishu Mason, Susan M. Grimes, Zilu Zhou, Billy T. Lau, Xiangqi Bai, Andrew Su, Xiao Tan, HoJoon Lee, Carlos J. Suarez, Quan Nguyen, George Poultsides, Nancy R. Zhang, Hanlee P. Ji (A) UMAP representation of dimensionally reduced data following batch-corrected graph-based clustering of all lymphocyte lineage cells annotated by cell types. (B) Heatmap depicting average expression of selected genes for each cell type. (C) UMAP representation annotated by condition. (D) Heatmap depicting cell states from CD8 T cells identified using EcoTyper NMF analysis, annotated by condition. (A-D) Data from seven mCRCs, five paired normal liver tissue and two paired PBMCs. (E) Violin plot depicting the expression of cytotoxicity gene signature in normal and tumor CD8 T cells with T-test p-value. Data from seven mCRCs, five paired normal liver tissue.
Funding
National Institutes of Health (NIH)
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...American Cancer Society (ACS)
Stanford University (SU)
U.S. Department of Energy (DOE)
History
ARTICLE ABSTRACT
The liver is the most frequent metastatic site for colorectal cancer. Its microenvironment is modified to provide a niche that is conducive for colorectal cancer cell growth. This study focused on characterizing the cellular changes in the metastatic colorectal cancer (mCRC) liver tumor microenvironment (TME).
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 sequencing (scRNA-seq). We validated our findings using multiplexed spatial imaging and bulk gene expression with cell deconvolution.
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 the worst prognosis in these patients.
We demonstrated that mCRC in the liver is characterized by transcriptional alterations of macrophages in the TME. Intercellular networking between macrophages and fibroblasts supports colorectal cancer growth in the immunosuppressed metastatic niche in the liver. These features can be used to target immune-checkpoint–resistant MSS tumors.
