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. [Display omitted] •Fibroblastic reticular cells (FRCs) generate T cell environments in lung cancer•FRCs in interconnected T cell environments promote protective antitumor immunity•Tumor FRCs resemble lymphoid organ fibroblasts in phenotype and function•Perivascular progenitors differentiate into CCL19-expressing tumor FRCs Specialized fibroblastic reticular cells (FRCs) underpin interconnected T cell environments with dedicated microenvironmental niches for FRC-T cell interaction, which promotes antitumor immunity in both human lung cancer and experimental murine lung tumors.