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
• cancer-associated fibroblast
• M2-like macrophage
• interleukin 6
• immunosuppression
• gastric cancer

Acknowledgments

The authors thank Prof. Dazhi Xu for his advice on the design and data analyses of this study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

X. Liu and J. Gao conceptualized and designed the study, H. Pan, X. Liu, and J. Gao provided the surgical specimen from gastric cancer patients, R. Wei, J. Song, H. Pan, and J. Gao performed experiments and analyzed and interpreted data, X. Liu and J. Gao supervised the study, R. Wei and J. Gao wrote the manuscript with input from all authors.

Data availability statement

The authors confirm that all data used and analyzed in the current study are available from the corresponding author on reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2024.2352179.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant [82203725].