Meflin-positive cancer-associated fibroblasts enhance tumour response to immune checkpoint blockade therapy

Abstract Cancer-associated fibroblasts (CAFs) are an integral component of the tumour microenvironment (TME). Most CAFs shape the TME toward an immunosuppressive milieu and attenuate the efficacy of immune checkpoint blockade (ICB) therapy. However, the detailed mechanism of how heterogeneous CAFs regulate tumour response to ICB therapy has not been defined. Here, we show that a novel CAF subset defined by Meflin, a glycosylphosphatidylinositol-anchored protein marker of mesenchymal stromal/stem cells, is associated with survival and favourable therapeutic response to ICB monotherapy in patients with non-small cell lung cancer (NSCLC). The prevalence of Meflin-positive CAFs positively correlated with CD4-positive T cell infiltration and vascularization within NSCLC tumours. Meflin deficiency and CAF-specific Meflin overexpression resulted in defective and enhanced ICB therapy responses in xenograft tumours in mice, respectively. These findings suggest the presence of a previously unknown CAF subset that promotes ICB therapy efficacy, which adds to our understanding of CAF functions and heterogeneity.