Key regulatory elements of the TGFβ-LRRC15 axis predict disease progression and immunotherapy resistance across cancer types.

Transforming growth factor-beta (TGFβ) has dual roles in cancer, initially suppressing tumors but later promoting metastasis and immune evasion. Efforts to inhibit TGFβ have been largely unsuccessful due to significant toxicity and indiscriminate immunosuppression. Leucine-rich repeat-containing protein 15 (LRRC15) is a TGFβ-regulated antigen expressed by cancer cells of mesenchymal origin and cancer-associated fibroblasts (CAFs). In preclinical studies, ablation of TGFβ-driven LRRC15+ CAFs enhances effector functions of CD8+ T cells. However, the pathobiological mechanisms associated with TGFβ's upregulation of LRRC15 expression in cancer cells remain unclear. Using an integrated approach combining functional compound screening with scRNA-seq, we reveal key genomic features regulating TGFβ's ability to increase LRRC15 expression on cancer cells. Construction of gene regulatory networks converged our analyses on four key genes (MMP2, SPARC, TGFβR2, and WNT5B) central to TGFβ-induced LRRC15 pathobiology in cancer cells. Validation of these genes in cell models and their use in predicting immunotherapy responses highlight their potential in refining immunotherapy strategies and personalizing cotreatment options.