Single-nucleus multimodal spatial transcriptomics reveals spatial colocalization of neoantigen-expressing tumor cells and cognate T cells
(1) Nagler A (2) Sud A (3) Ghannam JY (4) Pomerance L (5) Robles-Oteiza C (6) Afeyan AB (7) Weir JA (8) Russell AJC (9) Lu WS (10) Van Orden M (11) Sonnenholzner A (12) Marrero GJ (13) Gong Q (14) Kumar V (15) Huang K (16) Tu C (17) Lin E (18) Shim B (19) De Oliveira GR (20) Sellars MC (21) Yoon CH (22) Reardon DA (23) Choueiri TK (24) Olsen LR (25) Signoretti S (26) Ott PA (27) Braun DA (28) Oliveira G (29) Li S (30) Livak KJ (31) Hacohen N (32) Chen F (33) Wu CJ
Nagler, Sud, and Ghannam et al. developed a droplet-based single-nucleus spatial transcriptomics platform, Slide-GoTags, that integrates genotyping, TCR sequencing, and snRNAseq from the same frozen section to map neoantigen-specific immunity in situ. Slide-GoTags showed spatial co-localization of neoantigen-expressing tumor cells and their cognate T cell clonotypes, and distinct ICB-driven spatial immune landscapes. In melanoma, ccRCC, GBM, and ovarian cancer, Slide-GoTags identified IFN-driven niches enriched in activated or progenitor T cell clonotypes, with three TCR-neoantigen pairs in immunologically hot tumors.
Contributed by Shishir Pant
(1) Nagler A (2) Sud A (3) Ghannam JY (4) Pomerance L (5) Robles-Oteiza C (6) Afeyan AB (7) Weir JA (8) Russell AJC (9) Lu WS (10) Van Orden M (11) Sonnenholzner A (12) Marrero GJ (13) Gong Q (14) Kumar V (15) Huang K (16) Tu C (17) Lin E (18) Shim B (19) De Oliveira GR (20) Sellars MC (21) Yoon CH (22) Reardon DA (23) Choueiri TK (24) Olsen LR (25) Signoretti S (26) Ott PA (27) Braun DA (28) Oliveira G (29) Li S (30) Livak KJ (31) Hacohen N (32) Chen F (33) Wu CJ
Nagler, Sud, and Ghannam et al. developed a droplet-based single-nucleus spatial transcriptomics platform, Slide-GoTags, that integrates genotyping, TCR sequencing, and snRNAseq from the same frozen section to map neoantigen-specific immunity in situ. Slide-GoTags showed spatial co-localization of neoantigen-expressing tumor cells and their cognate T cell clonotypes, and distinct ICB-driven spatial immune landscapes. In melanoma, ccRCC, GBM, and ovarian cancer, Slide-GoTags identified IFN-driven niches enriched in activated or progenitor T cell clonotypes, with three TCR-neoantigen pairs in immunologically hot tumors.
Contributed by Shishir Pant
ABSTRACT: Improved methods to identify therapeutically relevant tumor neoantigens and their cognate T cells would aid the development of precision medicines for cancer. Here, we developed Slide-GoTags, a droplet-based single-nucleus spatial transcriptomics approach that characterizes neoantigen-specific immunity by integrating targeted transcript genotyping and T cell receptor (TCR) sequencing with single-nucleus RNA sequencing from the same slice of frozen tissue. Application of Slide-GoTags to mouse and human tumors revealed colocalization of clonally expanded, neoantigen-specific T cells with tumor cells expressing their cognate neoantigen. We also identified distinct spatial immune landscapes shaped by anti-PD1 or anti-CTLA4 blockade in mouse colorectal tumors. Across human tumor types, Slide-GoTags detected TCR-neoantigen interactions through spatial proximity and identified an enrichment of interferon-driven immunogenicity niches in immunologically 'hot' tumors compared to 'cold' tumors. These niches harbored three T cell clonotypes that colocalized with genotyped neoantigens, highlighting a spatially organized antitumor immune response. Collectively, Slide-GoTags establishes a framework for in situ mapping of T cell-tumor interactions directly from individual tissue.
Author Info:
(1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
(2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Harvard/MIT MD-PhD Program and Harvard Immunology PhD Program, Harvard Medical School, Boston, MA, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (7) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (8) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (11) LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. (12) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (13) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (14) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (15) Molecular Imaging Core (MIC), Dana-Farber Cancer Institute, Boston, MA, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (17) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (18) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (19) Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (20) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (21) Department of Surgical Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (22) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (23) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (24) Department of Bio and Health Informatics, Technical University of Denmark, Copenhagen, Denmark. Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark. (25) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (26) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (27) Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. (28) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (29) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (30) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (31) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (32) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (33) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. catherine_wu@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. catherine_wu@dfci.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. catherine_wu@dfci.harvard.edu. Division of Stem Cell Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Boston, MA, USA. catherine_wu@dfci.harvard.edu.
