m6A methylation regulators as predictors for treatment of advanced urothelial carcinoma with anti-PDL1 agent

Abstract

Purpose: Immune checkpoint blockade agents were shown to provide a survival advantage in urothelial carcinoma, while some patients got minimal benefit or side effects. Therefore, we aimed to investigate the prognostic value of m6A methylation regulators, and developed a nomogram for predicting the response to atezolizumab in urothelial carcinoma patients.Methods: A total of 298 advanced urothelial carcinoma patients with response data in the IMvigor210 cohort were included. Differential expressions of 23 m6A methylation regulators in different treatment outcomes were conducted. Subsequently, a gene signature was developed in the training set using the least absolute shrinkage and selection operator (LASSO) regression. Based on the multivariable logistic regression, a nomogram was constructed by incorporating the gene signature and independent clinicopathological predictors. The performance of the nomogram was assessed by its discrimination, calibration, and clinical utility with internal validation.Results: Six m6A methylation regulators, including IGF2BP1, IGF2BP3, YTHDF2, HNRNPA2B1, FMR1, and FTO, were significantly differentially expressed between the responders and non-responders. These six regulators were also significantly correlated with the treatment outcomes. Based on the LASSO regression analysis, the gene signature consisting of two selected m6A methylation regulators (FMR1 and HNRNPA2B1) was constructed and showed favorable discrimination. The nomogram integrating the gene signature, TMB, and PD-L1 expression on immune cells, showed favorable calibration and discrimination in the training set (AUC 0.768), which was confirmed in the validation set (AUC 0.755). Decision curve analysis confirmed the potential clinical usefulness of the nomogram.

The current landscape of m6A modification in urological cancers

“…Several studies indicated that IGF2BP3 was positively associated with the expression of PD-L1 in immune cells ( Cui et al, 2022 ), while FTO was just the opposite ( Deng et al, 2022 ). Kong et al (2022) found that in bladder cancer, the expression of HNRNPA2B1, FMR1, IGF2BP1, IGF2BP3, and YTHDF2 were significantly upregulated in the anti-PD-1 immunotherapy response group, while FTO expression was significantly downregulated. They also constructed a nomogram to predict the responsiveness of patients to atezolizumab monotherapy ( Kong et al, 2022 ).…”

“… Kong et al (2022) found that in bladder cancer, the expression of HNRNPA2B1, FMR1, IGF2BP1, IGF2BP3, and YTHDF2 were significantly upregulated in the anti-PD-1 immunotherapy response group, while FTO expression was significantly downregulated. They also constructed a nomogram to predict the responsiveness of patients to atezolizumab monotherapy ( Kong et al, 2022 ). But there were also other studies showing that FTO expression level was higher in bladder cancer patients who did not respond to immunotherapy ( Deng et al, 2022 ).…”

“…It was be validated that this correlation influenced treatment outcomes ( Su et al, 2021 ). FMR1 expression was significantly negatively associated with M2 macrophages, while decreased M0 macrophages in urothelial carcinoma tissues upon HNRNPA2B1 overexpression ( Kong et al, 2022 ). In ccRCC, Chen et al (2020b) confirmed that a higher m6A risk score leaded to a higher abundance of regulatory T cells (Tregs) and follicular helper T cells (Tfhs).…”

The role of RNA methylation in tumor immunity and its potential in immunotherapy

“…The use of m6A regulator inhibitors in enhancing ICB therapies has been extensively explored in recent studies [ 335 , 336 ]. m6A methylases play a crucial role in modulating the expression levels of PD-L1 and enhancing tumor sensitivity to anti-PD-1 and anti-CTLA-4 therapies, thereby improving the outcomes of ICB treatments [ 50 , 234 , 337 ].…”

Effect of the m6ARNA gene on the prognosis of thyroid cancer, immune infiltration, and promising immunotherapy

“…Dysregulation of m6A has been linked to cancer progression (25)(26)(27)(28)(29)(30). The effect of m6A-related genes on cancers has been widely studied, such as breast cancer (31), gastrointestinal cancer (32), urothelial carcinoma (33), gastric cancer (34). In pancreatic cancer, ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and inhibits chemosensitivity through activation of the mTOR pathway (35).…”