Characterization of Two Ferroptosis Subtypes With Distinct Immune Infiltration and Gender Difference in Gastric Cancer

Abstract

Background: Iron is an essential nutrient involved in the redox cycle and the formation of free radicals. The reprogramming of iron metabolism is the main link to tumor cell survival. Ferroptosis is an iron-dependent form of regulated cell death associated with cancer; the characteristics of ferroptosis in cancers are still uncertain. This study aimed to explore the application value and gender difference of ferroptosis in prognosis and immune prediction to provide clues for targeted therapy of gastric cancer.Methods: We comprehensively evaluated the ferroptosis levels of 1,404 gastric cancer samples from six independent GC cohorts based on ferroptosis-related specific genes and systematically correlated ferroptosis with immune cell infiltrating and gender characteristics. The ferroptosis score was constructed to quantify the ferroptosis levels of individual tumors using principal component analysis (PCA) algorithms.Results: We identified two distinct ferroptosis subtypes in gastric cancer, namely Subtype-A and Subtype-B. We found that male patients in Subtype-B had the worst prognosis in contrast with the other groups. Three sex hormone receptors (AR, ER, and PR) in Subtype-B tumor patients were higher than in Subtype-A tumor patients in GC, while the HER2 displayed an opposite trend. We developed a risk model termed ferroptosis score to evaluate ferroptosis levels within individual tumors. The low-ferroptosis score group was characterized by activation of immune cells and increased mutation burden, which is also linked to increased neoantigen load and enhanced response to anti-PD-1/L1 immunotherapy. The patients with a low-ferroptosis score showed a high microsatellite instability status (MSI-H) and had a higher response to immunotherapy. Furthermore, the patients with low-ferroptosis scores have a lower estimated IC50 in the several chemotherapy drugs, including paclitaxel, gemcitabine, and methotrexate.Conclusions: We revealed that sex hormone receptors and immune cell infiltration were markedly different between ferroptosis subtypes in GC patients. The results suggested that gender difference may be critical when the ferroptosis-related strategy is applied in GC treatment. Further, ferroptosis levels were identified with an extreme variety of prognosis and tumor immune characteristics, which might benefit GC individualized treatment.

Prognostic Model and Immune Infiltration of Ferroptosis Subcluster-Related Modular Genes in Gastric Cancer

“…Therefore, these results detailed the conditions and ways in which FRGs regulate GC development, which may be conducive to further study of immune escape surveillance. In addition, ferroptosis-related reactive oxygen species and iron uptake could lead to somatic nonsynonymous mutations and microsatellite instability, resulting in increasing immunogenicity and immune infiltrates [47,48], which was consistent with our findings.…”

Regulatory pathways and drugs associated with ferroptosis in tumors

“…Compared with non-malignant cells, the growth of cancer cells is strongly dependent on the micronutrient iron (ferrum in Latin), which is necessary for the ferroptosis process and can be inhibited by various iron-chelating agents. The excessive iron load may lead to ferroptosis in cancer patients [ 60 – 62 ], membrane transferrin receptor 1 (TFR1) can transport Fe 3+ ions into cells [ 63 ], was also recently identified as a biomarker for ferroptosis [ 63 ]. Under the action of DMT1, Fe 3+ is converted to Fe 2+ .…”

Role of ferroptosis and ferroptosis-related non-coding RNAs in the occurrence and development of gastric cancer

“…Studies have found that ferroptosis plays a critical role in the carcinogenesis and progression of GC ( Gomaa et al, 2019 ; Liu Y. et al, 2021 ). The levels of ferroptosis were related to a variety of prognosis and cancer immune characteristics, which might be conducive to the individualized treatment of GC ( Ma et al, 2021 ).…”