2025-07-10 バージニア工科大学(Virginia Tech)
<関連情報>
- https://news.vt.edu/articles/2025/07/research-fralinbiomed-prostatecancer.html
- https://aacrjournals.org/mcr/article-abstract/23/7/653/763052/Single-Cell-and-Spatial-Transcriptomics-Reveal-a
- https://www.nature.com/articles/s41467-023-36325-2
- https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00494-3
単一細胞および空間トランスクリプトミクスにより、前立腺がんの進行と転移を媒介する腫瘍関連マクロファージ亜集団が明らかになった Single-Cell and Spatial Transcriptomics Reveal a Tumor-Associated Macrophage Subpopulation that Mediates Prostate Cancer Progression and Metastasis
Shenglin Mei;Hanyu Zhang;Taghreed Hirz;Nathan Elias Jeffries;Yanxin Xu;Ninib Baryawno;Shulin Wu;Chin-Lee Wu;Akash Patnaik;Philip J. Saylor;David B. Sykes;Douglas M. Dahl
Molecular Cancer Research Published:July 02 2025
DOI:https://doi.org/10.1158/1541-7786.MCR-24-0791
Abstract
Tumor-associated macrophages (TAM) are a transcriptionally heterogeneous population, and their abundance and function in prostate cancer is poorly defined. We integrated parallel datasets from single-cell RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence to reveal the dynamics of TAMs in primary and metastatic prostate cancer. Four TAM subpopulations were identified. Notably, one of these TAM subsets was defined by the co-expression of SPP1+ and TREM2+ and was significantly enriched in metastatic tumors. The SPP1+/TREM2+ TAMs were enriched in the metastatic tumor microenvironment in both human patient samples and murine models of prostate cancer. The abundance of these SPP1+/TREM2+ macrophages was associated with patient progression-free survival. Spatially, TAMs within prostate cancer bone metastases were highly enriched within the tumor region, consistent with their protumorigenic role. Blocking SPP1 in the RM1 prostate cancer mouse model led to improved efficacy of anti–PD-1 treatment and increased CD8+ T-cell infiltration in tumor. These findings suggest that targeting SPP1+ TAMs may offer a promising therapeutic strategy and potentially enhance the effects of immune checkpoint inhibition in advanced prostate cancer.
Implications:
This study expands our understanding of the diverse roles of macrophage populations in prostate cancer metastases and highlights new therapeutic targets.
単一細胞および空間トランスクリプトーム解析による免疫抑制性ヒト前立腺腫瘍微小環境の解明 Dissecting the immune suppressive human prostate tumor microenvironment via integrated single-cell and spatial transcriptomic analyses
Taghreed Hirz,Shenglin Mei,Hirak Sarkar,Youmna Kfoury,Shulin Wu,Bronte M. Verhoeven,Alexander O. Subtelny,Dimitar V. Zlatev,Matthew W. Wszolek,Keyan Salari,Evan Murray,Fei Chen,Evan Z. Macosko,Chin-Lee Wu,David T. Scadden,Douglas M. Dahl,Ninib Baryawno,Philip J. Saylor,Peter V. Kharchenko & David B. Sykes
Nature Communications Published:07 February 2023
DOI:https://doi.org/10.1038/s41467-023-36325-2
Abstract
The treatment of low-risk primary prostate cancer entails active surveillance only, while high-risk disease requires multimodal treatment including surgery, radiation therapy, and hormonal therapy. Recurrence and development of metastatic disease remains a clinical problem, without a clear understanding of what drives immune escape and tumor progression. Here, we comprehensively describe the tumor microenvironment of localized prostate cancer in comparison with adjacent normal samples and healthy controls. Single-cell RNA sequencing and high-resolution spatial transcriptomic analyses reveal tumor context dependent changes in gene expression. Our data indicate that an immune suppressive tumor microenvironment associates with suppressive myeloid populations and exhausted T-cells, in addition to high stromal angiogenic activity. We infer cell-to-cell relationships from high throughput ligand-receptor interaction measurements within undissociated tissue sections. Our work thus provides a highly detailed and comprehensive resource of the prostate tumor microenvironment as well as tumor-stromal cell interactions.
ヒト前立腺癌骨転移巣には、作用可能な免疫抑制性微小環境が存在する Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment
Youmna Kfoury ∙ Ninib Baryawno ∙ Nicolas Severe ∙ … ∙ David B. Sykes ∙ Peter V. Kharchenko ∙ as part of the Boston Bone Metastases Consortium
Cancer Cell Published:October 15, 2021
DOI:https://doi.org/10.1016/j.ccell.2021.09.005
Highlights
- An immune-suppressive microenvironment characterizes bone metastatic prostate cancer
- Infiltrating T cells are exhausted and dysfunctional
- Inflammatory monocytes and M2 polarized macrophages are enriched and overexpress CCL20
- Disruption of the CCL20/CCR6 axes relieves T cell exhaustion and extends survival
Summary
Bone metastases are devastating complications of cancer. They are particularly common in prostate cancer (PCa), represent incurable disease, and are refractory to immunotherapy. We seek to define distinct features of the bone marrow (BM) microenvironment by analyzing single cells from bone metastatic prostate tumors, involved BM, uninvolved BM, and BM from cancer-free, orthopedic patients, and healthy individuals. Metastatic PCa is associated with multifaceted immune distortion, specifically exhaustion of distinct T cell subsets, appearance of macrophages with states specific to PCa bone metastases. The chemokine CCL20 is notably overexpressed by myeloid cells, as is its cognate CCR6 receptor on T cells. Disruption of the CCL20-CCR6 axis in mice with syngeneic PCa bone metastases restores T cell reactivity and significantly prolongs animal survival. Comparative high-resolution analysis of PCa bone metastases shows a targeted approach for relieving local immunosuppression for therapeutic effect.
