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Siglec-15 is a glyco-immune checkpoint in prostate cancer regulating immune evasion and metastasis

Nicoll Matthews, F. ZengiD, Kirsty HodgsoniD, Matthew Fisher, Ziqian PengiD, Libby BlencoeiD, Margarita Orozco‐MorenoiD, Ella P. DennisiD, Liancheng Lu, Michelle Anne LawsoniD, Shenglin MeiiD, David B. SykesiD, Dallas B. FliesiD, Richard BeatsoniD, Ning WangiD, Jennifer MunkleyiD

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Abstract

Prostate cancer is a leading cause of cancer-related mortality in men, and effective treatment options are limited for advanced and metastatic disease. The sialoglycan immune checkpoint Siglec-15 has emerged as a key mediator of tumour-associated immune suppression in several malignancies; however, its expression and functional role in prostate cancer remain poorly defined. Here, using dual immunofluorescence and immunohistochemistry, we demonstrate that Siglec-15 is expressed by prostate tumour epithelial cells, immunosuppressive macrophage phenotypes, and bone-resorbing osteoclasts within the tumour microenvironment. Mechanistically, we show that direct Siglec-15 receptor crosslinking, either by antibodies or tumour cell-derived conditioned medium, promotes monocyte-to-macrophage differentiation, generating macrophages with immunosuppressive and pathogenic phenotypes. Using therapeutic antibodies, we show that Siglec-15 blockade suppresses supernatant-induced monocyte to macrophage differentiation, allowing for the recovery of CD8 T-cell activation. Furthermore, we reveal that macrophage colony-stimulating factor (M-CSF) driven monocyte-derived macrophage differentiation is partially dependent on Siglec-15 signalling, with Siglec-15 blockade enhancing CD8 T-cell responses. In addition, anti-Siglec-15 treatment suppressed osteoclast differentiation, highlighting a dual role for Siglec-15 in prostate cancer immune suppression and bone remodelling. Consistent with these in vitro findings, therapeutic Siglec-15 blockade significantly reduced subcutaneous tumour growth in a CD8 T-cell-dependent manner and prolonged survival in a mouse model of prostate cancer metastasis. Together, these findings identify Siglec-15 as a central regulator of the prostate cancer glyco-immune axis, linking tumour-associated macrophage immune suppression with osteoclast-mediated bone remodelling, providing a compelling rationale for the clinical development of Siglec-15-targeted therapies for patients with advanced disease.

In-depth summary

Claude Opus 5.5 · xhigh effort · 7 Nov 2026 · from the full text of version 1 (10 Aug 2026) · CC BY 4.0

Siglec-15 is found on prostate tumour cells, macrophages and osteoclasts; antibody blockade reduced macrophage immunosuppression, osteoclast formation and tumour growth in mice (CD8+ T-cell-dependent).

The paper states that Siglec-15 expression and function in prostate cancer were poorly defined, and that individual Siglec-sialoglycan interactions in this disease were not yet mapped. It profiles Siglec-15 across tissue cohorts and tests therapeutic antibodies in primary human monocyte assays and two mouse models.

Key results

  1. ShownSiglec-15 protein is higher in prostate tumour epithelium than in normal prostate in three independent tissue microarray (TMA) cohorts.

    Cohort 2 (17 normal, 79 tumour): unpaired t test p<0.0001. Cohort 3 (60 patients, matched normal): paired t test p=0.0173. Cohort 1 (40 patients) also showed higher expression in cancer (p-value not given in text). · 2. Siglec-15 is upregulated in prostate tumour…; Figure legends

  2. ShownSiglec-15 is higher in bone metastases than in matched visceral metastases and is present across advanced CRPC models, with no clear dependence on androgen status.

    100 rapid-autopsy CRPC cases: bone vs visceral paired t test p<0.0002. In 39 LuCaP PDX models, AR-null vs AR-positive p=0.1188; intact vs castrated hosts p=0.4936 (no significant change). · 3. Siglec-15 is enriched in bone metastatic…; Figure legends

  3. ShownIn primary human monocyte cultures, Siglec-15 crosslinking drove differentiation; antibody blockade reduced live macrophages in tumour-conditioned medium and shifted M-CSF-driven macrophages toward lower CD206, PD-L1, CD86 and TGF-β1. T-cell proliferation and IFN-γ were partly restored.

    Crosslinking and flow assays used N=6 biological donors; conditioned-medium experiments N=3 biological x N=3 technical. Statistics are reported as significant, mostly without p-values in the text. · 4. Siglec-15 regulates monocyte differentiation…; 5. Siglec-15 coordinates M-CSF-driven macrophage…; Figure legends

  4. SuggestedAnti-Siglec-15 reduced osteoclast formation in vitro, slowed subcutaneous TRAMP-C2 tumour growth in a CD8+ T-cell-dependent way, and prolonged survival in a PC3 intracardiac bone-metastasis model.

    TRAMP-C2: 6 mice per group, two-way ANOVA p<0.0001 over 75 days, abolished by anti-CD8. PC3 model: n=20, log-rank p=0.0452. Osteoclast assays used mouse marrow precursors and RAW264.7 cells (TRAP counts). · 4. Siglec-15 regulates monocyte differentiation…; 5. Siglec-15 coordinates M-CSF-driven macrophage…; Figure legends

  5. SuggestedA five-gene signature (SIGLEC15, MRC1, TGFB1, CD274, CD86) derived from the in vitro assays was associated with worse survival and lower CD8A in TCGA-PRAD.

    High vs low signature (top vs bottom thirds): survival p=0.0278. Signature score was reported to correlate negatively with CD8A normalised to PTPRC (no coefficient given). · Transcriptomic analyses; 5. Siglec-15 coordinates M-CSF-driven macrophage…; Figure legends

Methods, data and reproducibility

The authors combined immunofluorescence and immunohistochemistry (H-score) on patient TMAs, PDX and bone-metastasis tissue with single-cell and bulk transcriptome re-analysis. They then ran primary human monocyte, macrophage, T-cell and osteoclast assays with therapeutic anti-Siglec-15 antibodies, plus two mouse tumour models.

  • Prostate cancer TMA cohorts 1 to 3 (normal vs tumour; cohort 3 matched pairs) · human · n = 40, 96 and 60 cases
  • CRPC rapid-autopsy TMA, matched bone and liver metastases · human · n = 100 cases
  • LuCaP patient-derived xenograft TMA · human tumours grown in mice · n = 39 models
  • Whole-slide immunofluorescence: primary tumours and bone metastasis tissue from rapid autopsy · human · n = 5 primary and 5 bone lesions; 20 bone autopsy cases provided
  • Published scRNA-seq of primary, advanced and bone-metastatic prostate cancer · human · GSE143791; OEP005136
  • TCGA-PRAD expression and survival data · human
  • Primary monocyte-derived macrophage and PBMC functional assays (leucocyte cones) · human · n = N=3 to 6 biological
  • TRAMP-C2 allograft and PC3 bone-metastasis mouse studies · mouse · n = 6 per group; 20 mice
Methods & tools
QuPath 0.6, Scanpy, Harmony, Scrublet, Seurat, GraphPad Prism 11.0.2, BD Accuri C6 Plus, NC318 and 5G12 anti-Siglec-15 antibodies, TCGA-PRAD, GSE143791
Reagents & environment
QuPath 0.6 and GraphPad Prism 11.0.2 are stated; the Scanpy pipeline settings (2,000 variable genes, 50 PCs, k=15) are given without package versions.
Reproducibility gaps
No code repository is given. The data statement says data are within the article and supplementary materials. Therapeutic antibodies were supplied by NextCure.
Limitations (5)
  • Downstream pathways linking Siglec-15 and M-CSF signalling to adaptive immune activation are incompletely understood; DAP12 involvement is only speculated. · stated by the authors
  • Endogenous sialoglycan ligands and their glycoprotein carriers in prostate cancer are not identified, and reports conflict on whether sialyl-Tn is a Siglec-15 ligand. · stated by the authors
  • Spatial multi-omics and glycomic profiling are still needed to define how tumour, immune and bone cells build the Siglec-15 niche. · stated by the authors
  • In vivo support rests on small studies: 6 mice per group in one subcutaneous model and a single bone-metastasis model with a borderline survival result (p=0.0452). · noted in this summary
  • The TCGA-PRAD signature comes from bulk expression and includes SIGLEC15 itself, so it cannot show that macrophages carry the survival or CD8A association. · noted in this summary

Read this if you work on glyco-immune checkpoints, tumour-associated macrophages or bone metastasis, and want early preclinical evidence for Siglec-15 as a prostate cancer target.

Citations
1

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