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. 2024 Nov 19:S0092-8674(24)01259-5.
doi: 10.1016/j.cell.2024.10.042. Online ahead of print.

Fibroblastic reticular cells generate protective intratumoral T cell environments in lung cancer

Lucas Onder  1 , Chrysa Papadopoulou  2 , Almut Lütge  3 , Hung-Wei Cheng  2 , Mechthild Lütge  2 , Christian Perez-Shibayama  2 , Cristina Gil-Cruz  2 , Angelina De Martin  2 , Lisa Kurz  2 , Nadine Cadosch  2 , Natalia B Pikor  4 , Regulo Rodriguez  5 , Diana Born  5 , Wolfram Jochum  5 , Pawel Leskow  6 , Andre Dutly  6 , Mark D Robinson  3 , Burkhard Ludewig  7
Affiliations

Fibroblastic reticular cells generate protective intratumoral T cell environments in lung cancer

Lucas Onder et al. Cell. .

Abstract

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.

Keywords: CD8 T cells; fibroblastic reticular cells; lung cancer; tumor microenvironment.

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Conflict of interest statement

Declaration of interests C.P.S., C.G.-C., H.-W.C., L.O., N.B.P., and B.L. are founders and shareholders of Stromal Therapeutics. L.O. and B.L. are members of the board of Stromal Therapeutics.

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