Abstract
While many anti-cancer modalities have shown potent efficacy in clinical practices, cancer prevention, timely detection, and effective treatment are still challenging. As a newly recognized iron-dependent cell death mechanism characterized by excessive generation of lipid peroxidation, ferroptosis is regarded as a potent weapon in clearing cancer cells. The cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) is the core target for ferroptosis regulation, the overexpression of which dictates downregulated sensitivity to ferroptosis in cancer cells. Hence, we elaborated the pan-cancer level bioinformatic study and systematically elucidated the role of intra-tumoral expression of SLC7A11 in the survival of cancer patients and potential immunotherapeutic response. Specifically, 25/27 (92.6%) cancers were featured with upregulated SLC7A11 expression, where SLC7A11 overexpression is a risk factor for worse overall survival in 8 cancers. We also validated SLC7A11 expression in multiple pancreatic cancer cell lines in vitro and found that it was upregulated in most pancreatic cancer cell lines (p < 0.05). Single-cell sequencing method revealed the SLC7A11 was majorly expressed in cancer cells and mononuclear cells. To further explore the function of SLC7A11 in cancer progression, we analyzed the influence on cell proliferation after the knockdown or knockout of SLC7A11 by either CRISPR or RNAi methods. Besides, the association between SLC7A11 and drug resistance was characterized using bioinformatic approaches as well. We also analyzed the association between the expression of SLC7A11 in multi-omics level and the intra-tumoral infiltration of immune cells based on cell annotation algorithms. Moreover, the relationship between SLC7A11 and the expression of MHC, immune stimulators, immune inhibitors as well as the response to immunotherapy was investigated. In addition, the SLC7A11 expression in colon adenocarcinoma, uterine corpus endometrial carcinoma, and stomach adenocarcinoma (STAD) is also positively associated with microsatellite instability and that in head and neck squamous cell carcinoma, STAD, and prostate adenocarcinoma is positively associated with neoantigen level, which further revealed the potential relationship between SLC7A11 and immunotherapeutic response.
Highlights
Cancer is the leading cause of human deaths in the world, which produces serious economic burdens both in developed and developing countries (Wu et al, 2019)
Because SLC7A11 has a low expression in normal tissues, ferroptosis is thought to occur in normal cells and could be a physiologic activity
The results showed that SLC7A11 expression is negatively associated with CD8+ T-cell infiltration in seven cancers (DLBC, esophageal carcinoma (ESCA), head-and-neck squamous cell carcinoma (HNSC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), testicular germ cell tumor (TGCT), and thyroid carcinoma (THCA)), suggesting the combination of ferroptosis induction and immunotherapy may be suitable in these cancers’ treatment (Supplementary Figure S3)
Summary
Cancer is the leading cause of human deaths in the world, which produces serious economic burdens both in developed and developing countries (Wu et al, 2019). An increasing number of studies reported that ferroptosis is involved in many pathophysiological conditions, including cardiovascular diseases, neurodegenerative diseases, and cancers (Jeong et al, 2017; Liang and Zhang, 2019; Mou et al, 2019). Many studies have reported that ferroptosis-induced cell death is an effective approach in killing cancer cells through reactive oxygen species (ROS) accumulation in cells, its clinical benefits still need clinical trials for verification (Friedmann Angeli et al, 2019; Hassannia et al, 2019). Wang et al demonstrated that PD-1-based immunotherapy combined with ferroptosis induction has a synergistic effect compared with single treatment. Given the low response rate of immunotherapy, ferroptosis induction may be a potent adjuvant modality in anti-cancer immunotherapy (Wang et al, 2019)
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