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Int J Biol Sci 2022; 18(5):1773-1794. doi:10.7150/ijbs.69808 This issue Cite

Research Paper

Ferroptosis-associated molecular classification characterized by distinct tumor microenvironment profiles in colorectal cancer

Wenqin Luo^1,2†, Weixing Dai^1,2†, Qingguo Li^1,2†, Shaobo Mo^1,2†, Lingyu Han^1,2, Xiuying Xiao³, Ruiqi Gu^1,2, Wenqiang Xiang^1,2, Li Ye^1,2, Renjie Wang^1,2, Ye Xu^1,2, Sanjun Cai^1,2, Guoxiang Cai^1,2✉

1. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
3. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
† Wenqin Luo, Weixing Dai, Qingguo Li and Shaobo Mo contributed equally to this work.

✉ Corresponding author: Guoxiang Cai, MD, PhD. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China. E-mail: gxcaifuscccom More

Abstract

Ferroptosis is a non-apoptotic form of cell death recognized in recent years. Nonetheless, the potential role of ferroptosis-associated genes in immune regulation and tumor microenvironment formation remains unknown. In this study, we characterized the ferroptosis-associated patterns of colorectal cancer through integrative analyses of multiple datasets with transcriptomics, genomics, and single-cell transcriptome profiling. Three distinct ferroptosis-associated clusters (FAC1, FAC2 and FAC3) were identified from 1251 CRC bulk samples, which were associated with different clinical outcomes and biological pathways. The TME characterization revealed that the three patterns were highly consistent with known immune profiles: immune-desert (FAC1), immune-inflamed (FAC2) and immune-excluded (FAC3), respectively. Ferroptosis-associated immune and stromal-activated genes were obtained and characterized by corresponding function in CRC tumorigenesis. Further single-cell analyses identified the ferroptosis-associated immune responding tumor cells and ferroptosis-associated stromal cells infiltration pattern. Based on the Fersig score, which was extracted from the ferroptosis phenotype-related signature, patients with lower Fersig score were characterized by prolonged survival time and effective immune responses. Collectively, we uncovered the ferroptosis-associated patterns associated with TME diversity and immune response phenotype. The Fersig we constructed could be the potential therapeutic target genes to improve the efficacy of patients' immunotherapy. The Fersig scoring scheme could enhance the understanding of TME infiltration associated with ferroptosis and prediction of immunotherapy efficacy.

Keywords: Colorectal cancer, Ferroptosis, Tumor microenvironment, Immune activation, Stromal cells infiltration, Myofibroblast, Immunotherapy.

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