Head and neck cancers (HNC) are the sixth most common group of cancers in the world. These cancers arise from cells that line the mouth, nose, throat, and the larynx. Ferroptosis is a type of cell death that is triggered by the accumulation of iron and reactive oxygen species. It has been linked to several diseases, including neurodegeneration, cancer, and inflammation. Recent studies have suggested that ferroptosis may be a significant factor in the effectiveness of immunotherapy for nasopharyngeal carcinoma (NPC). However, the role of ferroptosis in NPC immunotherapy is not yet fully understood and requires further research.
Now, in a rigorous new study published in Frontiers in Bioengineering and Biotechnology, Tsinghua University researcher Dr. Ming Shi, Dr. Jiangnan Du, Dr. Jingjing Shi, Dr. Yunchuanxiang Huang, Dr. Yan Zhao and Dr. Lan Ma found that ferroptosis-related genes could affect the tumor immune microenvironment of NPC. Through screening, the researchers found that the ferroptosis-related gene ATG5 could serve as a significant independent prognostic marker for HNSCC and NPC.
The research team showed that patients with higher levels of ATG5 expression in their tumors had a poorer prognosis compared to those with lower levels of ATG5 expression. Specifically, patients with high ATG5 expression had a significantly higher risk of disease recurrence and death. Furthermore, ATG5 has a strong correlation with multiple pathways in HNSCC and affects the therapeutic efficacy of ICB therapy. In addition to its potential as a prognostic biomarker, the study also found that ATG5 plays a critical role in the development of HNSCC and NPC by promoting ferroptosis. The authors demonstrated that ATG5 is necessary for the accumulation of iron and reactive oxygen species in cancer cells, which ultimately leads to their death. The drug IC50 prediction showed ATG5 high expression HNSCC samples were more sensitive to G2M checkpoint inhibitors. Moreover, they demonstrated that ATG5 is necessary for the accumulation of iron and reactive oxygen species in cancer cells, which ultimately leads to their death. This discovery highlights the importance of ferroptosis in the development and progression of HNSCC and NPC.
Furthermore, the study found that ATG5 expression was positively correlated with PD-L1 and PD-L2 expression in HNSCC and NPC, which are markers of tumor-induced immune suppression. This suggests that ATG5 may be involved in the regulation of the immune microenvironment in HNSCC and NPC, potentially impacting the response to immunotherapy. The study also found that ATG5 expression was positively correlated with the G2M checkpoint signaling pathway in HNSCC. G2M checkpoint is an important regulatory mechanism in eukaryotic cells that regulates the normal operation of the cell cycle, ensuring the integrity of the number of chromosomes, and most tumor cells have a G1 checkpoint, thus, controlling the proliferation of tumor cells to the G2M stage is a feasible tumor treatment regimen.
The researchers used GDSC, the largest publicly available pharmacogenomics database, to predict the sensitivity of G2M checkpoint inhibitor drugs in high and low ATG5 expression HNSCC samples, which based on sample transcriptomes. The results showed ATG5 high expression samples were more sensitive to G2M checkpoint inhibitors. This suggests that G2M checkpoint inhibitors may have a therapeutic effect on ATG5 high expression HNSCC and NPC. The researchers also found that the abundance of CD8+ T cells decreased in ATG5 high expression HNSCC patients, and the abundance of Tregs increased. CD8+ T cells screen and eliminate invaders, and if CD8+ T cell infiltration is less than 2.2% in tumor, the risk of developing disease progression after surgery will be 4-fold higher. The better overall survival and immune infiltration levels in group 2 suggested the important role of ferroptosis-related genes in HNSCC and NPC.
In summary, using cutting-edge technology and methodical assays Dr. Lan Ma and colleagues found that ATG5 is a novel prognostic biomarker for head and neck squamous cell carcinoma (HNSCC) and nasopharyngeal carcinoma (NPC) and has a strong correlation with multiple pathways in HNSCC. It also found that ATG5 has a strong correlation with PD-L1/PD-L2 expression, G2M checkpoint signaling pathway, CD8+ T cells, and Tregs in HNSCC and NPC, which suggest that ATG5 may be a promising therapeutic target for HNSCC and NPC. The research highlights the importance of ferroptosis in the development and progression of HNSCC and NPC, and shows that ATG5 is a novel prognostic biomarker for these cancers.
Shi M, Du J, Shi J, Huang Y, Zhao Y, Ma L. Ferroptosis-related gene ATG5 is a novel prognostic biomarker in nasopharyngeal carcinoma and head and neck squamous cell carcinoma. Frontiers in Bioengineering and Biotechnology. 2022 ;10.