GEO series

Evolution of myeloid-mediated immunotherapy resistance in prostate cancer

GSE274229 Homo sapiens; Mus musculus Expression profiling by high throughput sequencing 52 samples Submitted 2024/12/04 Platform GPL24676Platform GPL24247

Summary

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.

Published in

Sialylated glycoproteins suppress immune cell killing by binding to Siglec-7 and Siglec-9 in prostate cancer

Wen RM, Stark JC, Marti GEW et al. · The Journal of clinical investigation 2024 · PMID 39436703 · doi:10.1172/JCI180282

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Direct links to NCBI, no account and no request form: the whole study as GSE274229_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 52 samples. Raw sequencing reads are also available from ENA.

Whole study · RAW.tar ↓ Series matrix ↓ All supplementary files ↗ Raw reads on ENA ↗

Also filed as BioProject PRJNA1143590 and SRA study SRP523989. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 39436703) ↗

Study design

40 conditions, each sampled once — no replicated groups

Read from the first 40 of 52 sample titles: 40 distinct titles with little repetition. Check it against the sample list below before relying on it.

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