T cell-mediated curation and restructuring of tumor tissue coordinates an effective immune response
John W. Hickey,
Maximillian Haist,
Nina Horowitz,
Chiara Caraccio,
Yuqi Tan,
Andrew J. Rech,
Marc-Andrea Baertsch,
Xavier Rovira-Clavé,
Bokai Zhu,
Gustavo Vazquez,
Graham Barlow,
Eran Agmon,
Yury Goltsev,
John B. Sunwoo,
Markus Covert,
Garry P. Nolan
Affiliations
John W. Hickey
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Maximillian Haist
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Nina Horowitz
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
Chiara Caraccio
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Yuqi Tan
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Andrew J. Rech
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Marc-Andrea Baertsch
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Xavier Rovira-Clavé
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Bokai Zhu
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Gustavo Vazquez
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Graham Barlow
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Eran Agmon
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Center for Cell Analysis and Modeling, University of Connecticut Health, Farmington, CT 06032, USA
Yury Goltsev
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
John B. Sunwoo
Department of Otolaryngology, Head and Neck Surgery, Stanford Cancer Institute, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
Markus Covert
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
Garry P. Nolan
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Corresponding author
Summary: 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.
