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

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.

Signatures of EMT, immunosuppression and inflammation of primary and recurrent human cutaneous squamous cell carcinoma at single-cell resolution

“…Recently, a subtype of TAMs with SPP1 + characteristics was reported to carry angiogenesis-related properties and was linked to tumour metastasis(Cheng et al, 2021; Liu et al, 2022; Qi et al, 2022). In our study, SPP1 + CD209 high and SPP1 + CD209 low TAMs were identified as two subpopulations of SPP1 + TAMs, which showed an elevated proportion in recurrent cSCC (Fig.…”

“…A recent study revealed that SPP1 + macrophages may prevent the infiltration of lymphocytes, which further reduces the efficacy of PD-L1 treatment(Qi et al, 2022). Moreover, SPP1 + macrophages were reported to carry out angiogenesis, which was positively correlated with EMT markers and related to tumour metastasis(Georgoudaki et al, 2016; Cheng et al, 2021; Liu et al, 2022; Qi et al, 2022).…”

“…A recent study revealed that SPP1 + macrophages may prevent the infiltration of lymphocytes, which further reduces the efficacy of PD-L1 treatment(Qi et al, 2022). Moreover, SPP1 + macrophages were reported to carry out angiogenesis, which was positively correlated with EMT markers and related to tumour metastasis(Georgoudaki et al, 2016; Cheng et al, 2021; Liu et al, 2022; Qi et al, 2022). Herein, SPP1 + TAMs tended to express a global protumour characteristic in recurrent cSCC, including lower phagocytosis and inflammation scores, as well as higher angiogenesis scores, which may be the critical mechanism of cSCC recurrence.…”

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

“…This result is supported by recent studies in primary CRC, which identified positive correlation between fibroblasts and SPP1 + macrophages. Their presence was associated with poor survival and accompanied by reduced lymphocyte infiltration (65, 66).…”

The Role of Osteopontin in Tumor Progression Through Tumor-Associated Macrophages

“…The results reported by Li et al indicated that OPN secreted by TAMs upregulated PD-L1 expression through the NF-kB/P65 pathway in an NSCLC mouse model, and TOPN was positively correlated with PD-L1 expression in NSCLC patients (19). FAP + fibroblasts and SPP1 + macrophages are the major components of TME in colorectal cancer, which are characterized as major contributors to the desmoplastic tumor structure and immunotherapy resistance against PD-L1 in colorectal cancer (80). Some pieces of evidence have demonstrated that OPN infiltrating macrophages facilitated tumor cell survival and angiogenesis in glioblastoma multiforme (GBM) (81).…”