Background

Lung cancer, an extremely heterogeneous disease, caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined [29]. LUAD is one of the important sub-types of lung cancer with an increasing incidence [28]. Despite great efforts having been made in develo** novel treatments but still received a poor prognosis with 5-year survival rates vary from 4% to 17% [13]. Patients with histologically similar tumors may have different outcomes due to molecular differences. Therefore, there is an urgent need to find new sensitive biomarkers for predicting survival of LUAD patients. Compared with a single biomarker, integrating multiple biomarkers into a signature would greatly improve prognostic prediction.

Iron is an essential trace element for human body. Its deficiency or excess can influence many biological processes [23]. Cancer cells exhibit an enhanced dependence on iron for growth and are dramatically more susceptible to iron depletion than non-cancer cells [21]. However, highly increased iron concentrations result in cell death through membrane lipid peroxidation, termed ferroptosis [12, 31]. Ferroptosis is an iron-dependent pathway of cell death that was discovered in recent years [18, 19]. The induction of cell death is known to be an viable approach for cancer therapy. Ferroptosis has also been identified as a potential prevention or therapeutic strategies to trigger cancer cell death, especially for malignancies that are resistant to traditional treatments [20]. Some studies have noticed the potential function of ferroptosis and iron metabolism in lung cancer development and suppression, but the detailed regulators remain unclear. Meanwhile, lncRNAs are defined as non-protein-coding transcripts larger than 200 nucleotides to distinguish them from small noncoding RNAs [16]. LncRNAs are participated in various biological purposes, such as immune, metabolism, infection, and so on. LncRNAs have been shown to function as master regulators in various disease processes including cancer [11]. Remarkably, it has been found that lncRNAs are the crucial mediators in the regulation of ferroptosis and iron metabolism in cancer [17]. In routine clinical practice, pathologic staging is a vital prognostic determinant of LUAD. However, clinical outcomes differ among patients at the same stage, indicating that the traditional staging system cannot adequately predict the prognosis of patients. Biomarkers related to tumor diagnosis and prognosis urgently need to be developed. Disturbances in iron metabolism cause excessive intracellular iron storage and may induce ferroptosis [4]. Impaired ferroptosis is implicated in various pathological conditions [7]. Due to the important role of ferroptosis and iron metabolism in cancer, its related lncRNA has also attracted a lot of attention [24].

To the best of our knowledge, this study is the first one to identify and comprehensively analyze prognostic FIRLs in LUAD. This signature based on 7 FIRLs provides a useful tool to supplement the traditional clinical prognostic factors, and guides prognostic prediction and therapeutic decisions. Additionally, we provide a FIRLs-related nomogram combining clinical factors to predict the OS of LUAD patients with an effective quantitative approach.

Immune regulation plays a crucial part in the progression of LUAD. The number and proportion of infiltrating immune cells are recognized as important factors affecting cancer progression and immunotherapy response and associated with patient prognosis. According to the tumor immunoediting hypothesis [9], less immunogenic cancer cells are selected for during tumor development in immune-competent hosts, to evade antitumor immune responses. This may result in increased immunosuppressive cells (e.g., regulatory T cells), decreased immunoreactive cells (e.g., helper T cells). Thus, we hypothesized that patients in different risk groups would have different immunotherapeutic responses. Results found that high-risk LUAD patients had higher NK cells infiltration and lower fractions of Mast cells and helper T cells than low-risk patients. The above results suggest that the poorer prognosis of high-risk patients is due to higher immunosuppression and lower immunoreactivity in the tumor microenvironment, and these differences contribute to tumor progression. Checkpoint inhibitor-based immunotherapies have improved the survival of patients of advanced malignancies [14]. Significant differences in the expression of immune checkpoints between high and low risk groups suggested the differences in the sensitivity to immunotherapies. Furthermore, findings in some cancer suggest that TMB may predict clinical response to immune checkpoint inhibitors [26]. In this study, we found that patients with LUAD in high risk group had higher TMB levels which was related to the immune effect.

However, several limitations of our study should be taken into consideration. Firstly, our study was mainly based on data from TCGA in which most patients were White or Asian. Caution must be taken when extrapolating our findings to patients from other ethnicities. Secondly, external validation of the signature in large-scale multicenter cohorts is necessary. Thirdly, further functional experiments in our laboratory will be required to verify findings and elucidate the roles of FIRLs in LUAD. In addition to its excellent performance in differentiating LUAD from normal lung, the role of the signature in differentiating normal lung, pulmonary nodules, and small cell lung cancer remains to be further elucidated.

In summary, the 7-FIRLs signature is a potential tool for predicting the OS rate of LUAD patients. Importantly, the signature might be associated with immune infiltration levels and even the TMB scores. We expect this robust signature will provide clues on biological behaviors as well as prognostic characteristics in clinical tests.

Conclusions

By and large, we successfully constructed a strong predictive signature of ferroptosis and iron metabolism which may serve as a new biomarker and therapeutic target affecting the progression of LUAD. Meanwhile, the signature helps researchers deeply understand the correlation between ferroptosis and tumourigenesis. Furthermore, this study provides a promising avenue for future anti-tumor immunotherapy.