A novel CAF population coordinates hyper-suppressive regulatory T cell recruitment and localization in lung cancer

Abstract

Across many solid tumor types, cancer-associated fibroblasts (CAFs) are abundant and heterogeneous, with distinct subpopulations exerting immunomodulatory functions. Here we identify a novel population of immunomodulatory CAFs (imCAFs) in primary lung adenocarcinoma and pulmonary metastases, characterized by cell adhesion molecule L1-like (CHL1) expression and enriched in immune regulation and chemokine signaling programs. Through single-cell and spatial transcriptomics, we demonstrate that imCAFs are spatially colocalized with CXCR3+ regulatory T (Treg) cells, a hyper-suppressive subset accumulating at the tumor border. imCAFs produce CXCL9, driving CXCR3+ Treg cell recruitment and promoting an immunosuppressive microenvironment. CXCR3+ Treg cells display enhanced proliferative and suppressive capacity and are transcriptionally distinct from CXCR3− counterparts. Genetic ablation of Cxcr3 in Treg cells or Cxcl9 in stromal cells reduces Treg cell accumulation, enhances CD8+ T cell activation and decreases tumor burden. Analogous CHL1+ imCAF-like fibroblasts in human non-small cell lung cancer colocalize with Treg cells, and elevated CHL1 expression is associated with reduced cytotoxicity and decreased progression-free survival, highlighting the imCAF–CXCL9–CXCR3+ Treg axis as a promising therapeutic target. Ringham et al. identify immunomodulatory cancer-associated fibroblasts that influence regulatory T cell dynamics in lung cancer.