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Target macrophage SPP1 promtes CD8 T cell infiltrations

ABSTRACT: SPP1 in tumor associated macrophages (TAM) can inhibit the infiltration of CD8 T cells, promote tumor growth, and reduce the efficacy of ICI immunotherapy. Single cell (sc)-RNA sequencing data showed markedly increased CD8 T cells in the tumor tissues of SPP1fl/fl-Lyz2-icre mice compared to control SPP1fl/fl mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE296902 | GEO | 2026/06/30

REPOSITORIES: GEO

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Target macrophage SPP1 promotes CD8 T cell infiltrations

Project description:SPP1 in tumor associated macrophages (TAM) can inhibit the infiltration of CD8 T cells, promote tumor growth, and reduce the efficacy of ICI immunotherapy. RNA sequencing data showed diffrential expressed genes and enrichment pathway in the bone marrow derived macrophages from SPP1fl/fl-Lyz2-icre mice compared to control SPP1fl/fl mice.

2026-06-30 | GSE297153 | GEO

SPP1 represents a therapeutic target that promotes the progression of esophageal squamous cell carcinoma by driving M2 macrophage infiltration

Project description:Background: Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME). However, the crosstalk between esophageal squamous cell carcinoma (ESCC) cells and TAMs remains largely unexplored. Methods: Clinical samples and the TCGA database were used to evaluate the relevance of SPP1 and TAM infiltration in ESCC. Mouse models were constructed to investigate the roles of macrophages educated by SPP1 in ESCC. Macrophage phenotypes were determined using qRT‒PCR and immunohistochemical staining. RNA sequencing was performed to elucidate the mechanism. Results: Increasing expression of SPP1 correlated with M2-like TAM accumulation in ESCC, and they both predicted poor prognosis in the ESCC cohort. Knockdown of SPP1 significantly inhibited the infiltration of M2 TAMs in xenograft tumors. In vivo mouse model experiments showed that SPP1-mediated education of macrophages plays essential roles in the progression of ESCC. Mechanistically, SPP1 recruited macrophages and promoted M2 polarization via CD44/PI3K/AKT signaling activation and then induced VEGFA and IL6 secretion to sustain ESCC progression. Finally, blockade of SPP1 with RNA aptamer significantly inhibited tumor growth and M2 TAM infiltration in xenograft mouse models. Conclusions: This study highlights a SPP1-mediated crosstalk between ESCC cells and TAMs in ESCC. SPP1 could serve as a potential target in ESCC therapy.

2024-09-09 | GSE256360 | GEO

Proteomic changes in the colon of mice with epithelial specific deletion of Apc or Apc/Dhps

Project description:C57BL/6 mice with a tamoxifen (TAM)-inducible disruption of Apc (CDX2P-CreERT2;Apc fl/fl) or Apc and Dhps (CDX2P-CreERT2;Apc fl/fl;Dhps fl/fl) were injected or not with one intraperitoneal injection 4.5 mg/kg TAM. After 35 days, the following colon biopsies were harvested: normal tissues from mice that did not receive TAM, non-tumor tissues from mice treated with TAM, and tumors from mice treated with TAM. Biopsies from 5 mice were collected for the following sample groups: (1) Apc Control; (2) Apc/Dhps Control; (3) Apc+TAM non-tumor; (4) Apc/Dhps+TAM non-tumor; (5) Apc+TAM tumor; (6) Apc/Dhps+TAM tumor

2025-09-12 | PXD061596 | Pride

mRNA transcriptome sequencing of siglecf low macrophages from tumor lungs of chimeric mice that were intranasally injected with Ad-Cre

Project description:The transcriptional profiling of siglecf low macrophages from tumor lungs of Tmem173fl/fl→KrasLSL-G12D/+Lkb1fl/fl (WTKL) and Tmem173fl/fl;Lyz2-Cre→KrasLSL-G12D/+Lkb1fl/fl (LYZKL) chimeric mice.

2025-11-29 | GSE301096 | GEO

Target macrophage SPP1 promotes CD8 T cell infiltrations

Project description:Target macrophage SPP1 promotes CD8 T cell infiltrations

| PRJNA1262905 | ENA

Target macrophage SPP1 promtes CD8 T cell infiltrations

Project description:Target macrophage SPP1 promtes CD8 T cell infiltrations

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Characterization of Spp1-TAP and Mer2-TAP interactomes

Project description:Histone H3K4 methylation is a feature of meiotic recombination hotspots shared by many organisms including plants and mammals. Meiotic recombination is initiated by programmed double strand break (DSB) formation that in budding yeast is directed in gene promoters by histone H3K4 di/trimethylation. This histone modification is indeed recognized by Spp1, a PHD-finger containing protein that belongs to the conserved histone H3K4 methyltransferase Set1 complex. During meiosis, Spp1 binds H3K4me and recruits a DSB protein, Mer2, to promote DSB formation close to gene promoters. How Set1C and Mer2 related functions of Spp1 are connected is not clear.

2018-01-30 | PXD007590 | Pride

p-FADD-CD8+T cell axis determines hepatocellular carcinoma response to immune checkpoint inhibitors

Project description:The heterogenicity of hepatocellular carcinoma (HCC) remains a key obstacle in turning the majority of ‘immune-cold’ tumors ‘hot’ for effective immune checkpoint inhibitors (ICIs). Through analyzing the naturally-existed ‘hot’ HCC variants, we identified fas-associated death domain (FADD) as a key molecule upregulated in patients with dense tumor-filtrating CD8+T cells and better response to ICIs. Apart from the canonical role in apoptosis pathway, our data showed that CRISPR knockout of hepatoma-intrinsic Fadd led to increased tumor weights in immunocompetent but not immunodeficient mice, accompanied with decreased numbers and IFN-γ/TNF-ɑ production of tumor-filtrating CD8+T cells. Mechanistically, phosphorylated FADD translocated into cell nucleus, where it interacted with Sam68 to upregulate NF-κB transcription of CCL5, thereby promoted CD8+T cell tumor infiltration. Interestingly, anti-PD1 triggered FADD phosphorylation by CD8+T cell-derived IFN-γ/TNF-ɑ in ICI-sensitive, but not resistant tumors. Sequential FADD activation through genetic or pharmacologic approaches to orchestrate p-FADD-CD8+T cell axis therefore overcame ICI resistance in ICI-resistant orthotopic and spontaneous HCC mouse models in vivo. Taken together, our findings may provide insights into the combinatory immunotherapy approaches for the majority of HCC patients in the future.

2025-07-07 | PXD057519 | Pride

Evolution of myeloid-mediated immunotherapy resistance in prostate cancer

Project description:Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs), partly because there are immunosuppressive myeloid cells in tumours. However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts (SPP1hi-TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8+ T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1hi-TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1hi-TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1hi-TAM-mediated immunosuppression in CD8+ T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1hi-TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1hi-TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.

2024-12-04 | GSE274229 | GEO

SPP1+ macrophages in HR+ breast cancer are associated with tumour-infiltrating lymphocytes.

Project description:Breast cancer, categorised into hormone receptor-positive (HR+), HER2-positive (HER2+), and triple-negative (TNBC) subtypes, exhibits varied outcomes based on the number of tumour-infiltrating lymphocytes (TILs). Increased TIL levels are associated with better outcomes in HER2+ and TNBC, while HR+ individuals with high TIL levels show shorter survival but greater neoadjuvant chemotherapy response. To explore the divergent roles of TIL levels across various subtypes and their effect on immune cell composition, we employed single-cell RNA sequencing on 31 patients with breast cancer. HR+ breast cancer with high TIL levels (TIL-high) revealed increased SPP1+ macrophages, increased SPP1 expression in other monocytes/macrophages (mono/macro) subgroups, and enriched pathways associated with extracellular matrix (ECM) remodelling in mono/macro. Moreover, cell–cell interaction analyses revealed enhanced SPP1, MIF, and FN1 signalling in the interaction between SPP1+ macrophages and T-cells in TIL-high HR+ breast cancer. Spatial transcriptomics data highlighted the close proximity of SPP1+ macrophages, CD8+ T-cells, and CD4+ T-cells in TIL-high HR+ breast cancer. Our findings unveil the novel influence of SPP1+ macrophages on T-cells in TIL-high HR+ breast cancer, potentially explaining the poor prognosis and offering insights for targeted interventions.

2024-10-09 | GSE261774 | GEO

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