M6A regulator expression patterns predict the immune microenvironment and prognosis of non-small cell lung cancer

Background: The m6A methylation modification is one of the most common mRNA modifications, and involved in a variety of biological processes, such as cell death, cancer stem cell formation and tumorigenesis. Increasing evidences have demonstrated that the expression patterns of m6A regulators are significantly correlated with PD-L1 level some solid tumors, but few study has explored the function of m6A regulators in the immune microenvironment and prognosis in non-small cell lung cancer (NSCLC).

Methods: Survival analysis was independently conducted for 20 m6A regulators to explore their prognostic value in NSCLC, and then the prognostic risk model based on m6A regulator expression profiles is built to stratify NSCLC patients. Also, the correlation analysis between immune infiltrating cells and m6A regulators is used to reveal the impact of m6A on immune microenvironment of NSCLC. Furthermore, to explore the function of m6A as biomarker of anit-PD-L1 therapeutic effect, we explored the associations of tumor mutation burden (TMB) and PD-L1 levels to 20 m6A regulator expression patterns in NSCLC.

Results: First, the expressions of 20 m6A regulators in NSCLC tissues were significantly increased compared to normal tissues. Survival analysis revealed that three genes, METTL3, HNRNPC and VIRMA, were markedly correlated to the prognosis of NSCLC patients. In particular, cox regression analysis verified that METTL3 could be used as an independent prognostic factor to predict the survival rate of NSCLC patients. Second, the risk prognostic model built on seven m6A regulators can effectively stratify NSCLC patients, and the low-risk subgroup had better prognosis compared to high-risk group. Finally, a few m6A regulators showed significant associations with immune microenvironment, as well as TMB and PD-L1 level, suggesting that the m6A RNA methylation is indicative of therapeutic effect of anti-PD-L1 treatment.

Conclusion: Our study identified some m6A regulatory factors as independent risk factors for the prognosis of NSCLC, and the expression patterns of m6A regulators are also correlated to the immune infiltration, as well as TMB and PD-L1 level in NSCLC. The m6A regulators could be used as biomarkers indicative of immunotherapy to NSCLC patients.