Lung cancer is the malignant tumor that causes the most deaths among cancers, and metastasis is the main cause of death. Whereas the underlying mechanisms that affect metastasis have not been fully explored. Tumor microenvironment (TME) is a key factor in tumor initiation and progression, and its expression is related to immune function, immune evasion and immunotherapy. Moreover, the prognostic roles of IRGs in various cancers are well documented. Accordingly, the present study selected 9 key IRGs for NSCLC metastasis, and constructed a risk score predictive model that could aid in the prediction of metastasis risk and decision-making in clinical practice.
Furthermore, the key genes were mainly enriched in the immune-related signaling pathways, which indirectly provides a rationale of targeted and immunotherapy for the treatment of metastatic tumors. Currently tyrosine kinase inhibitors (TKIs) have been proven to be a standard therapy for advanced NSCLC patients with driver gene mutations. And immune checkpoint inhibitors (ICIs) have become an effective first-line treatment for driver gene mutation-negative patients(8). Additionally, the 5-year overall survival (OS) rate of metastatic patients has increased from less than 5% to over 30% treated with TKIs and 20% treated with ICIs(9).
In this study, younger age, higher T stage, and higher risk score were related to an increased metastasis risk in NSCLC patients. Among them, age was one protective factor for metastasis. This may be due to the degeneration of body functions in elderly patients. Consequently, tumors were often indolent, asymptomatic, slow growing and clinically silents, and fewer metastatic events occurred. The tumor nodes metastasis (TNM) staging system is the main tool to forecast survival and guide treatment in cancer patients. The study found that larger tumors with deeper infiltration are probably more aggressive, which correspondences with literature.
This study developed a risk score model for NSCLC metastasis based on 9 immune genes, which would contribute to the development of novel diagnostic markers and potential therapeutic targets. Of these, PDK1 is an AGC family protein kinase, and is always overexpressed in tumors and inhibits cell apoptosis to promote cancer progress. It can also regulates the immunotherapy response by affecting the components of TME(10). PROC gene mutation has been reported to be associated with plasma protein C deficiency, an important factor for controlling blood clotting and inflammation, representing an increased risk for venous thromboembolism(11). IL11 encodes interleukin (IL)-11, a cytokine belonging to IL-6 family, which has anti-inflammation properties. It can promote tumor invasion and metastasis by activating relevant pathways(12), and is associated with poor prognosis in multiple cancer(13, 14). SH2D1B is a member of the SH2 domain protein family that mainly modulates the functions of SLAMF receptor family. Research has found that high SH2D1B expression can activate macrophage phagocytosis and anti-tumor immunity in high-risk neuroblastoma patients(15). S100A5 is a member of the S100 protein family. It can weaken the killing power of effector T cells on cancer cells and promote tumor proliferation and invasion, and is negatively correlated with the effects of immunotherapy(16). AGT encodes angiotensinogen, which is the precursor of angiotensin peptides. It can also activate epithelial-mesenchymal transition (EMT), which has been related to tumor proliferation, migration and poor prognosis(17). WFDC2 belongs to WAP domains protein family. Its high expression in tumors represents a immune inhibitory function on tumor cells. In addition, it can inhibited cancer metastasis through suppression of EMT, leading to better survival(18, 19). CRHR2 is a G protein-coupled receptor. Its low expression was linked to distant metastasis and poor prognosis(20, 21). EREG encodes a member of the epidermal growth factor (EGF) protein family, which is a ligand for the epidermal growth factor receptor (EGFR). Its up-regulation activates EGFR and related signaling pathways, and is associated with tumor metastasis as well as poorer oncologic outcomes(22, 23). The above literature suggests that the genes contained in the model all affect tumor infiltration and migration, which are similar to the conclusions of the present study. However, there are limited relevant researches on some genes and some conclusions were inconsistent. Therefore, the specific mechanism of these genes in the tumor occurrence and development needs to be further studied.
TME is comprised of blood vessels, immune cells, signaling molecules, fibroblasts and extracellular matrix. The immunosuppressive status of TME suggests a major barrier for the efficacy of ICIs. In this research, the high-risk group displayed a higher degree of immune cells infiltration and a stronger immunogenicity, indicating that patients in the high-risk group might benefit more from immunotherapy as a consequence.
Several limitations of this study should be acknowledged. The number of metastasis NSCLC cases in TCGA database was limited, and the database lacks several vital information, such as clinical treatment and molecular subtypes, which could decrease the clinical practicability. And further research is needed to collect relevant data from clinical cases and other databases. In addition, only various bioinformatics methods were utilized to select the key genes in the present study, whereas the mechanisms and interactions of its action remain ambiguous, which may affect the reliability of the conclusion. And in-depth investigations are thus warranted to confirm these results.