Characterizing spatial immune architecture in metastatic melanoma using high-dimensional multiplex imaging.

Area of Science:

• Immunology
• Oncology
• Spatial Biology

Background:

• Metastatic melanoma survival is improved by immune checkpoint inhibitors (ICIs).
• Resistance to ICIs arises from immunosuppressive tumor immune microenvironments (TIME).
• Spatial architecture of TIME components may offer prognostic biomarkers and therapeutic targets.

Purpose of the Study:

• To investigate stage-specific changes in the spatial organization of the melanoma TIME.
• To identify spatial biomarkers associated with survival in metastatic melanoma.
• To explore how immune cell interactions and inflammatory neighborhoods influence treatment response.

Main Methods:

• High-dimensional spatial profiling of Stage III and Stage IV melanoma tissue microarrays (TMAs).
• Utilized imaging mass cytometry (IMC) and multiplex immunofluorescence (mIF) to analyze TIME.
• Quantified cellular neighborhoods and spatial interactions, assessing associations with survival via Cox models.

Main Results:

• Stage IV tumors displayed altered immune landscapes with increased inflammatory neighborhoods and depleted B and NK cells compared to Stage III.
• Positive survival correlations were found for CTL-Th, NK-T, and B-NK cell interactions.
• Macrophage aggregation and B-Th cell clustering in inflammatory regions correlated with worse outcomes.

Conclusions:

• Melanoma TIME exhibits stage-specific immune composition and spatial organization shifts.
• Spatial patterns of immune coordination, particularly involving CTLs, NK cells, and B cells, are strong survival predictors.
• Identified spatial biomarkers can refine patient stratification and guide combination immunotherapy strategies.