Meiser and Knolle et al. showed that a distinct population of immunostimulatory MHC-IIhiCCR7neg cDC1 through the CXCL9/CXCL10–CXCR3 axis formed clusters with TCF1+CD8+ T cells at the stroma–tumor interface. These niches resulted in cDC1-mediated TCF1+CD8+ T cell activation and subsequent effector T cell differentiation that enabled protective anti-cancer immunity. Spatial organization of cDC1-CD8+ T cell interactions was conserved in human cancers, and higher expression of the CXCL9+CCR7neg cDC1 gene signature and their clustering with intratumoral CD8+ T cells positively correlated with survival across multiple cancers and with response to ICB.
Contributed by Shishir Pant
ABSTRACT: Type 1 conventional dendritic cells (cDC1) can support T cell responses within tumors but whether this determines protective versus ineffective anti-cancer immunity is poorly understood. Here, we use imaging-based deep learning to identify intratumoral cDC1-CD8(+) T cell clustering as a unique feature of protective anti-cancer immunity. These clusters form selectively in stromal tumor regions and constitute niches in which cDC1 activate TCF1(+) stem-like CD8(+) T cells. We identify a distinct population of immunostimulatory CCR7(neg) cDC1 that produce CXCL9 to promote cluster formation and cross-present tumor antigens within these niches, which is required for intratumoral CD8(+) T cell differentiation and expansion and promotes cancer immune control. Similarly, in human cancers, CCR7(neg) cDC1 interact with CD8(+) T cells in clusters and are associated with patient survival. Our findings reveal an intratumoral phase of the anti-cancer T cell response orchestrated by tumor-residing cDC1 that determines protective versus ineffective immunity and could be exploited for cancer therapy.
Author Info: (1) Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany. (2) Institute for Artificial Intelligence in Medicine & Healthcare
Author Info: (1) Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany. (2) Institute for Artificial Intelligence in Medicine & Healthcare, School of Medicine, TUM, Munich, Germany; Institute for Diagnostic and Interventional Radiology, School of Medicine, TUM, Munich, Germany; Department of Computing, Imperial College London, London, UK. (3) Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany. (4) Institute of Animal Physiology and Immunology, School of Life Science, TUM, Freising, Germany; Institute of Virology, School of Medicine, TUM, Munich, Germany. (5) Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany. (6) Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany. (7) Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany. (8) Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, TUM, Munich, Germany. (9) Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany; Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, TUM, Munich, Germany. (10) Department of Otolaryngology Head and Neck Surgery, School of Medicine, TUM, Munich, Germany. (11) Institute of Pathology, School of Medicine, TUM, Munich, Germany. (12) Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany. (13) Department of Otolaryngology Head and Neck Surgery, School of Medicine, TUM, Munich, Germany. (14) Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany. (15) Institute of Pathology, School of Medicine, TUM, Munich, Germany; Comparative Experimental Pathology, School of Medicine, TUM, Munich, Germany; German Cancer Consortium, partner site Munich, Munich, Germany. (16) Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, TUM, Munich, Germany. (17) Department of Otolaryngology Head and Neck Surgery, School of Medicine, TUM, Munich, Germany. (18) Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knll-Institute, Jena, Germany; Institute of Microbiology, Faculty of Biological Sciences, Friedrich Schiller University, Jena, Germany. (19) Institute for Diagnostic and Interventional Radiology, School of Medicine, TUM, Munich, Germany. (20) Institute for Artificial Intelligence in Medicine & Healthcare, School of Medicine, TUM, Munich, Germany; Department of Computing, Imperial College London, London, UK; Chair for Artificial Intelligence in Medicine and Healthcare, School of Medicine and School of Computation, Information and Technology, Klinikum rechts der Isar, TUM, Munich, Germany. (21) Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany; Institute of Molecular Immunology, School of Life Science, TUM, Freising, Germany; German Center for Infection Research, Munich site, Munich, Germany. (22) Institute for Artificial Intelligence in Medicine & Healthcare, School of Medicine, TUM, Munich, Germany; Institute for Diagnostic and Interventional Radiology, School of Medicine, TUM, Munich, Germany; Department of Computing, Imperial College London, London, UK. (23) Institute of Molecular Immunology, School of Medicine, Technical University of Munich (TUM), Munich, Germany. Electronic address: j.boettcher@tum.de.
