Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer

TLDR

Colorectal cancer is a common malignancy with limited non‑surgical treatments, and profiling the tumor microenvironment can uncover therapeutic targets. The study aims to profile 54,103 cells from tumor and adjacent tissues to characterize cellular composition and elucidate the origin and regulation of tumor‑enriched cell types in CRC. The authors performed single‑cell and spatial transcriptomic profiling of 54,103 cells from tumor and adjacent tissues to map cellular composition and interactions. The study found that FAP+ fibroblasts and SPP1+ macrophages are positively correlated and spatially co‑localized in CRC, their interaction is driven by chemerin, TGF‑β, and IL‑1, and high expression of either cell type predicts poorer response to anti‑PD‑L1 therapy, suggesting that disrupting this interaction could enhance immunotherapy efficacy.

Abstract

Abstract Colorectal cancer (CRC) is among the most common malignancies with limited treatments other than surgery. The tumor microenvironment (TME) profiling enables the discovery of potential therapeutic targets. Here, we profile 54,103 cells from tumor and adjacent tissues to characterize cellular composition and elucidate the potential origin and regulation of tumor-enriched cell types in CRC. We demonstrate that the tumor-specific FAP + fibroblasts and SPP1 + macrophages were positively correlated in 14 independent CRC cohorts containing 2550 samples and validate their close localization by immuno-fluorescent staining and spatial transcriptomics. This interaction might be regulated by chemerin, TGF-β, and interleukin-1, which would stimulate the formation of immune-excluded desmoplasic structure and limit the T cell infiltration. Furthermore, we find patients with high FAP or SPP1 expression achieved less therapeutic benefit from an anti-PD-L1 therapy cohort. Our results provide a potential therapeutic strategy by disrupting FAP + fibroblasts and SPP1 + macrophages interaction to improve immunotherapy.