T cell-mediated curation and restructuring of tumor tissue coordinates an effective immune response.

Antigen-specific T cells traffic to, are influenced by, and create unique cellular microenvironments. Here we characterize these microenvironments over time with multiplexed imaging in a melanoma model of adoptive T cell therapy and human patients with melanoma treated with checkpoint inhibitor therapy. Multicellular neighborhood analysis reveals dynamic immune cell infiltration and inflamed tumor cell neighborhoods associated with CD8⁺ T cells. T cell-focused analysis indicates T cells are found along a continuum of neighborhoods that reflect the progressive steps coordinating the anti-tumor immune response. More effective anti-tumor immune responses are characterized by inflamed tumor-T cell neighborhoods, flanked by dense immune infiltration neighborhoods. Conversely, ineffective T cell therapies express anti-inflammatory cytokines, resulting in regulatory neighborhoods, spatially disrupting productive T cell-immune and -tumor interactions. Our study provides in situ mechanistic insights into temporal tumor microenvironment changes, cell interactions critical for response, and spatial correlates of immunotherapy outcomes, informing cellular therapy evaluation and engineering. [Display omitted] • CODEX multiplexed imaging of human and mouse, immunotherapy-treated melanomas • Tumor-specific T cells cause inflamed tumor phenotype and unique cell neighborhoods • T cell phenotype influences capacity to make effective tumor-killing neighborhoods • Potent therapy creates larger, linked areas of inflamed tumor and immune infiltrate Hickey et al. discovered that tumor-specific T cells induce tumor inflammation and establish progressive inflammatory environments. Effective therapies exhibit compartmentalized immune infiltration, co-located with T cell and inflamed tumor zones, emphasizing the need for therapeutic T cells to be designed to curate local and distal microenvironments. [ABSTRACT FROM AUTHOR]