Colorectal Cancer Metastases in the Liver Establish Immunosuppressive Spatial Networking between Tumor-Associated SPP1+ Macrophages and Fibroblasts.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
04 01 2023
04 01 2023
Historique:
received:
29
06
2022
revised:
01
09
2022
accepted:
12
10
2022
pubmed:
15
10
2022
medline:
6
1
2023
entrez:
14
10
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36239989
pii: 709778
doi: 10.1158/1078-0432.CCR-22-2041
pmc: PMC9811165
doi:
Substances chimiques
Immunosuppressive Agents
0
Osteopontin
106441-73-0
SPP1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
244-260Subventions
Organisme : NCI NIH HHS
ID : U54 CA261717
Pays : United States
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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