The Treg-fibroblast axis shapes the immunosuppressive tumor microenvironment in colorectal cancer

The tumor microenvironment (TME) is a critical regulator of cancer progression and therapeutic response. Cancer-associated fibroblasts (CAFs) are a heterogeneous and significant component of the TME. Among CAFs, the subset marked by leucine-rich repeat containing 15 (LRRC15) is enriched in tumors and has been implicated in immune suppression and resistance to immunotherapy. However, the functional interactions of LRRC15+ CAFs within the TME, particularly with regulatory T cells (Tregs), remain incompletely understood. While it has been reported that LRRC15+ CAFs are induced by TGFbeta signaling, we show in murine models that blockade of TGFbeta pathways does not reverse LRRC15 expression, indicating that maintenance of LRRC15+ CAFs in the tumor microenvironment is not solely dependent on TGFbeta. Using multi-omics and spatial analysis of human tumor samples, we define the specific molecular profile of LRRC15+ CAFs, which strongly correlates with Treg abundance and shows frequent proximity to Tregs within the TME. Finally, functional studies in mouse models demonstrate that Treg depletion leads to pronounced remodeling and reduction of the LRRC15+ CAF compartment. Together, these findings reveal a Treg-LRRC15+ fibroblast axis that actively shapes the immunosuppressive landscape of colorectal cancer via Treg maintenance of CAF phenotype and suggest that targeting this interaction may disrupt stromal-mediated immune evasion in immuno-oncology. AbbVie Disclosure Statement: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.