Single-Cell and Spatial Transcriptomics Reveal a Tumor-Associated Macrophage Subpopulation that Mediates Prostate...

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• Tumor-associated macrophages (TAMs) exhibit heterogeneity, with poorly defined roles in prostate cancer progression.
• Understanding TAM dynamics is crucial for developing effective prostate cancer therapies.

Purpose of the Study:

• To investigate TAM heterogeneity and dynamics in primary and metastatic prostate cancer.
• To identify specific TAM subsets and their association with disease progression and therapeutic response.

Main Methods:

• Integrated single-cell RNA-sequencing, spatial transcriptomics, and multiplex immunofluorescence.
• Analyzed human patient samples and murine models of prostate cancer.
• Investigated the therapeutic potential of targeting SPP1+ TAMs in a mouse model.

Main Results:

• Identified four distinct TAM subpopulations, with SPP1+/TREM2+ TAMs enriched in metastatic prostate cancer.
• SPP1+/TREM2+ TAM abundance correlated with poorer patient progression-free survival.
• Blocking SPP1 enhanced anti-PD-1 therapy efficacy and CD8 T cell infiltration in a preclinical model.

Conclusions:

• SPP1+/TREM2+ TAMs represent a pro-tumorigenic subset in prostate cancer metastases.
• Targeting SPP1+ TAMs is a potential therapeutic strategy to improve outcomes in advanced prostate cancer.
• This approach may enhance the efficacy of immune checkpoint inhibitors like anti-PD-1.