Ferroptosis Patterns Correlate with Immune Microenvironment Characterization in Gastric Cancer

Xiaotao Jiang,1,2 Fan Liu,2,3 Peng Liu,1,2 Yanhua Yan,1,2 Shaoyang Lan,1 Kunhai Zhuang,1,4 Yufeng Liu,5 Kailin Jiang,1,2 Yuancheng Huang,1,2 Kechao Nie,1,2 Zhihua Zheng,1,2 Jinglin Pan,6 Junhui Zheng,1,2 Fengbin Liu,1,4 Shijie Xu,5 Peiwu Li,1 Yi Wen1 1Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 2First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 3Zhaoqing Hospital of Chinese Medicine Affiliated to Southern Medical University, Zhaoqing, Guangdong, People’s Republic of China; 4Baiyun Hospital of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 5Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 6Department of Gastroenterology, Hainan Provincial Hospital of Traditional Chinese Medicine, Haikou, Hainan, People’s Republic of ChinaCorrespondence: Peiwu Li; Yi Wen Email doctorlipw2@163.com; 421491922@qq.comObjective: We aimed to build a ferroptosis-based classifier to characterize the molecular features of gastric cancers (GC) and investigate the relationship between different ferroptosis patterns and GC tumor microenvironment (TME).Methods: Based on the genomic and clinical information from TCGA portal and GEO database, non-negative matrix factorization (NMF) was used to identify ferroptosis subtypes in GC patients. In order to estimate the ferroptosis levels, we established ferroptosis subtype score (FSS) to quantify ferroptosis patterns and ferroptosis potential index (FPI) by principal component analysis (PCA). The correlations of different ferroptosis patterns with TME cell-infiltrating characteristics (including immune cell infiltration, immune checkpoints expression levels, tumor mutational burden (TMB) and immunotherapy response) were systematically analyzed.Results: Two ferroptosis subtypes, C1 (with lower FSS) and C2 (with higher FSS), were determined. C2 displayed a significantly lower FPI than C1. Besides, C2 was associated with diffuse subtype while C1 with intestinal subtype. As for TME characteristics, C2 was in accordance with the immune-excluded phenotype as it showed more active immune and stromal activities but lower TMB, less probability of immunotherapy response and poorer prognosis. C1 was linked to immune-inflamed phenotype as it had lower stromal activities but increased neoantigen load, enhanced response to immunotherapy and relatively better prognosis.Conclusion: The systematic assessment of ferroptosis patterns and ferroptosis levels presented in our study implied that ferroptosis serves as an important factor in the formation of TME, which may expand the understanding of TME and provide a novel perspective for the development of targeted immunotherapeutic strategies for GC patients.Keywords: ferroptosis, gastric cancer, immune cell infiltration, tumor microenvironment, immunotherapy