CRATER tumor niches facilitate CD8⁺ T cell engagement and correspond with immunotherapy success

Area of Science:

• Immunology
• Oncology
• Spatial Biology

Background:

• T cell-mediated tumor killing is fundamental to immunotherapy efficacy.
• Understanding the spatial organization of immune cells within tumors is critical for optimizing cancer treatments.

Purpose of the Study:

• To identify specific microenvironmental domains that facilitate the immune response during cancer immunotherapy.
• To investigate the role of these domains in T cell engagement and tumor killing in melanoma.

Main Methods:

• Long-term in vivo imaging and high-resolution spatial transcriptomics in zebrafish melanoma models.
• Multiplex imaging of human melanoma biopsies.
• Analysis of T cell interactions and spatial distribution within tumor microenvironments.

Main Results:

• Identification of Cancer Regions of Antigen Presentation and T cell Engagement and Retention (CRATERs) at stroma-melanocyte boundaries in both zebrafish and human melanoma.
• CRATERs exhibit high density of CD8+ T cells and antigen-recognition molecules, facilitating prolonged T cell-melanoma cell interactions.
• CRATER expansion and density correlate with activated T cell accumulation, tumor killing, and clinical response to immunotherapy (including immune checkpoint blockade).

Conclusions:

• CRATERs represent key functional niches for T cell-mediated tumor killing during immunotherapy.
• The density and characteristics of CRATERs may serve as a predictive biomarker for immunotherapy response in melanoma patients.