Fibroblastic reticular cells generate protective intratumoral T cell environments in lung cancer
Stringent control of T cell activity in the tumor microenvironment is essential for the generation of protective antitumor immunity. However, the identity, differentiation, and functions of the cells that create critical fibroblastic niches promoting tumor-infiltrating T cells remain elusive. Here, we show that CCL19-expressing fibroblastic reticular cells (FRCs) generate interconnected T cell environments (TEs) in human non-small cell lung cancer, including tertiary lymphoid structures and T cell tracks. Analysis of the FRC-T cell interactome in TEs indicated molecular networks regulating niche-specific differentiation of CCL19-expressing fibroblasts and T cell activation pathways. Single-cell transcriptomics and cell fate-mapping analyses in mice confirmed that FRCs in TEs originate from mural and adventitial progenitors. Ablation of intratumoral FRC precursors decreased antitumor T cell activity, resulting in reduced tumor control during coronavirus vector-based immunotherapy. In summary, specialized FRC niches in the tumor microenvironment govern the quality and extent of antitumor T cell immunity.
Authors
- Pawel Leskow
- Almut Lütge (ORCID: https://orcid.org/0000-0003-1104-727X)
- Wolfram Jochum (ORCID: https://orcid.org/0000-0001-6170-2020)
- Cristina Gil‐Cruz (ORCID: https://orcid.org/0000-0001-5285-6503)
- Mechthild Lütge (ORCID: https://orcid.org/0000-0001-9011-5319)
- Mark D. Robinson (ORCID: https://orcid.org/0000-0002-3048-5518)
- Burkhard Ludewig (ORCID: https://orcid.org/0000-0002-7685-573X)
- Lucas Onder (ORCID: https://orcid.org/0000-0003-1471-412X)
- Angelina De Martin (ORCID: https://orcid.org/0000-0002-9056-8075)
- Chrysa Papadopoulou (ORCID: https://orcid.org/0000-0002-3909-7378)
- Regulo Rodriguez
- Hung‐Wei Cheng (ORCID: https://orcid.org/0000-0003-1740-0337)
- Natalia Pikor (ORCID: https://orcid.org/0000-0002-6564-4232)
- Christian Perez‐Shibayama (ORCID: https://orcid.org/0000-0001-9335-4120)
- Nadine Cadosch
- André Dutly
- Lisa Kurz (ORCID: https://orcid.org/0000-0002-0557-2636)
- Diana Born
Institutions
- SIB Swiss Institute of Bioinformatics (CH)
- Kantonsspital St. Gallen (CH)
- University Hospital of Zurich (CH)
Publication Details
- Journal
- Cell
- Published
- 2024-11-19
- DOI
- https://doi.org/10.1016/j.cell.2024.10.042
- Citations
- 70
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 19.78
Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Krebsliga Schweiz