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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261774 | GEO | 2024/10/09

REPOSITORIES: GEO

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Project description:There is clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SET ER/PR index to measure gene expression microarray probe sets that were correlated with hormone receptors (ESR1 and PGR) and robust to pre-analytical and analytical influences. We tested SET ER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SETER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 to 0.955, p = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SETER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript. We tested SET ER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SET ER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.485, 95% CI 0.265 to 0.889, p = 0.019; OS: HR 0.314, 95% CI 0.155 to 0.637, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SET ER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript.

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

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