Tumor associated T cell actication by ICB is one of the most successful approaches for cancer immunotherapy and expected to improve the prognosis of LGG patients. However, it is poorly studied in LGGs. Recently, growing efforts have focused on the m6A RNA methylation and it’s impacts on cancer immune editing 50. Here, we developed the m6Ascore to quantify the m6A methylation modification patterns in individuals and a dual-targeted strategy including anti-IL-6 and ICB to reverse T cell exhaustion for those patients with high-m6Ascore LGGs.
Based on the existing evidence of m6A methylation modification network, 24 m6A regulators were involved in the study and stratified the the tumor samples. DEGs among the distinct m6A phenotypes were identified and considered as a m6A relevant signature in LGG, which was a biomarker designed to classify m6A modification patterns. The expressions of m6A regulators in gene cluster B were significantly higher than in the other two clusters, and the expressions of immune-checkpoints and gatheration of suppressive cells in gene cluster A&C were remarkably decreased. Patients in gene cluster B experienced the worst clinical outcomes.Then, we constructed a scoring scheme termed ‘m6Ascore’ to quantify the m6A methylation modification patterns which can act as an indipendent prognostic biomarker for LGG patients. In addition, the results of our analyses showed the correlation between m6Ascore with the genomic aberrations, especialy with IDH1, EGFR and TP53 mutation status. Then, we determined whether m6Ascore can predict immunotherapy benefit in LGG. It is observed that there were less predicted ICB benefits in m6Ascore-high group compared with m6Ascore-low group. Thus, we expected to explore potential strategies to make those non-benefit patients benefit from immunotherapy.
IL-6, a pleiotropic cytokine, was recognized as a key cytokine to promote inflammation at first 51. Recent studies has suggested that IL-6/JAK/STAT3 inhibited functional maturation of DC and suppressed effector T cells which blocked anti-tumor immunity 52. IL-6 promoted M2 Mϕs polarization 53, 54 and tumors with high IL-6 expression with infiltration of PD1+CD8+ T cells and M2 Mϕs predicted poor prognosis 55. In our study, we used cell line expression profiles and their drug sensitivity results to predict the sensitive drugs of TCGA-LGG with high m6Ascore by machine learning, and found the key pathway, IL6/JAK/STAT3, related to TME modulation. However, anti-IL-6 therapy showed the modest efficacy to synergize with ICB out of the patients with high ower m6Ascore LGGs, suggesting that there are certain mechanisms to protect the downstreams of IL-6 from anti-IL-6 therapy.
Multiple studies have revealed the significant impacts of TNF superfamily on macrophage activation and their co-stimulation of T cells to promote anti-tumor immunity 56, 57. Thus, we analyzed the expression profile of Mϕs treated with IL-6, and found that IL-6 significantly up-regulated the expression of cd40, tnfsf4, tnfsf9, tnfsf14 and tnfsf15. Then, we found that the expression level of CD40 and TNFSF9 was significantly higher in m6Ascore-high group than the other groups when the expression of IL-6 remained same low level at different m6Ascore groups. These results illustrate a phynomenon that anti-IL-6 monotherapy might not fully reverse macrophage-mediated immunosuppression. Dual-targeting of CD40/TNFSF9 and IL-6 might cooperate immunotherapy of LGGs.
In summary, our study established the m6Ascore to quantifying the m6A methylation modification in individuals. For LGG patients with high m6Ascores, we found some therapeutic drugs to avoid overtreatment and chemotherapy resistance. In the meanwhile, our findings suggested that dual-targeted stratergy including anti-IL-6 and ICB might trigger anti-tumor immunity for the patients with high-m6Ascore LGGs which offered opportunities for facilitating T-cell based immunotherapy against LGGs.