Single-cell and spatial transcriptomics reveal SPP1-CD44 signaling drives primary resistance to immune checkpoint...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immune checkpoint inhibitors (ICIs) are crucial for advanced renal cell carcinoma (RCC) treatment.
• Primary resistance to ICIs significantly limits treatment efficacy in RCC.
• Mechanisms underlying primary ICI resistance in RCC are not fully understood.

Purpose of the Study:

• To investigate tumor-immune interactions driving primary resistance to ICIs in RCC.
• To identify signaling pathways involved in ICI resistance in renal cell carcinoma.
• To unravel the molecular mechanisms of primary ICI resistance in RCC.

Main Methods:

• Integration of single-cell RNA sequencing and spatial transcriptomics.
• Analysis of clinical RCC samples.
• Application of computational methods: cell-cell communication networks, pseudotime, and GSEA.

Main Results:

• Increased SPP1-CD44 signaling in the primary resistance group compared to the sensitive group.
• SPP1-CD44 interactions impaired antigen presentation and suppressed chemokine/cytokine pathways.
• SPP1-CD44 signaling activated MAPK in exhausted CD8+ T cells, exacerbating T cell exhaustion and driving ICI resistance.

Conclusions:

• SPP1-CD44 signaling mediates tumor-immune interactions contributing to ICI resistance in RCC.
• Disruption of SPP1-CD44 signaling may offer a strategy to overcome primary ICI resistance.
• Provides a theoretical basis for novel therapeutic approaches in renal cell carcinoma.