Abstract 5537: MGA mutation status affect tumor immunomicroenvironment and predict the effect of immune check point inhibitor: From NSCLC to pan-cancers analysis
Authors: Ji Wenxiang , Lu Shun 
Published: June 2022

Background: A critical and challenging process in immunotherapy is to identify cancer patients who could benefit from immune checkpoint inhibitors (ICIs). Exploration of predictive biomarkers could help to maximize the clinical benefits. Thus, this research aimed to explore the underlying association between MGA mutation and cancer immunotherapy in pan-cancers.

Methods: Clinical data and sequencing data from published studies were collected and consolidated to analyze the association between MGA mutation status and efficacy of ICI therapy in NSCLC and pan-cancers cohort respectively. To better understand the role of MGA in cancer immunotherapy, the correlation between MGA and several immunotherapeutic biomarkers (TMB, NAL and MSI) was investigated. Furthermore, the correlation between MGA and tumor immune-microenvironment, such as immune cell infiltration, immune related genes, and underlying signaling pathways were analyzed.

Results: MGA-MUT was enriched in patients responding to ICI therapy. In the pool NSCLC cohort (N = 262), significant differences were detected between MGA-MUT and MGA_WT patients regarding objective response rate (ORR, 52.2% vs 23.9%, p= 0.006), disease control rate (DCR,86.9% vs. 61.2%, p = 0.013), durable clinical benefit (DCB, 69.6% versus 36.7%, p= 0.003), and mPFS in MGA-MUT was 15.1 months much longer than 4.3 months in the MGA_WT (adjusted p=0.008). In the pool pan-cancers cohort (N = 1576), significant overall survival advantage was observed in MGA-MUT patients (HR = 0.67 [95%CI, 0.51 to 0.88], adjusted p= 0.007). In subgroup analysis, the survival advantage of MGA-MUT vs. MGA-WT was prominent and consistent across gender, drug type, cancer type. But the survival advantage was dramatically different between two age groups. In younger group(age≤60), the survival benefit receiving ICI treatment was prominent in MGA-MUT patients compared with Wildtype (mOS not reach [NR] vs 19 m, HR = 0.48 [95% CI 0.31-0.73], adjusted p = 0.002), but the discrepancy was not recurrent in the elders (age&gt;60). In further exploring, we found that MGA mutation status was close connected higher tumor mutation burden, more neoantigen load, and higher MSI score. The CD8+ T cell and NK cell infiltration in MGA-MUT tumors were higher than its counterpart. Further GSEA analysis revealed enhanced anti-tumor immunity in MGA-MUT tumor, especially the cytosolic DNA sensing pathway recurrent in multiple cancer types.

Conclusions: This research investigated the immunotherapeutic value of MGA in pan-cancers, indicating that MGA-MUT could serve as a potential predictive biomarker for immune checkpoint inhibitors, and providing preliminary evidence regarding the function of MGA mutation and its role in anti-tumor immunity.

Citation Format: Wenxiang Ji, Shun Lu. MGA mutation status affect tumor immunomicroenvironment and predict the effect of immune check point inhibitor: From NSCLC to pan-cancers analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5537.