CPT1C-positive cancer-associated fibroblast facilitates immunosuppression through promoting IL-6-induced M2-like phenotype of macrophage

Abstract

Cancer-associated fibroblasts (CAFs) exhibit remarkable phenotypic heterogeneity, with specific subsets implicated in immunosuppression in various malignancies. However, whether and how they attenuate anti-tumor immunity in gastric cancer (GC) remains elusive. CPT1C, a unique isoform of carnitine palmitoyltransferase pivotal in regulating fatty acid oxidation, is briefly indicated as a protumoral metabolic mediator in the tumor microenvironment (TME) of GC. In the present study, we initially identified specific subsets of fibroblasts exclusively overexpressing CPT1C, hereby termed them as CPT1C⁺CAFs. Subsequent findings indicated that CPT1C⁺CAFs fostered a stroma-enriched and immunosuppressive TME as they correlated with extracellular matrix-related molecular features and enrichment of both immunosuppressive subsets, especially M2-like macrophages, and multiple immune-related pathways. Next, we identified that CPT1C⁺CAFs promoted the M2-like phenotype of macrophage in vitro. Bioinformatic analyses unveiled the robust IL-6 signaling between CPT1C⁺CAFs and M2-like phenotype of macrophage and identified CPT1C⁺CAFs as the primary source of IL-6. Meanwhile, suppressing CPT1C expression in CAFs significantly decreased IL-6 secretion in vitro. Lastly, we demonstrated the association of CPT1C⁺CAFs with therapeutic resistance. Notably, GC patients with high CPT1C⁺CAFs infiltration responded poorly to immunotherapy in clinical cohort. Collectively, our data not only present the novel identification of CPT1C⁺CAFs as immunosuppressive subsets in TME of GC, but also reveal the underlying mechanism that CPT1C⁺CAFs impair tumor immunity by secreting IL-6 to induce the immunosuppressive M2-like phenotype of macrophage in GC.

Keywords: Carnitine palmitoyltransferase 1C; M2-like macrophage; cancer-associated fibroblast; gastric cancer; immunosuppression; interleukin 6.