Immune dysregulation underpins radioresistance in nasopharyngeal carcinoma (NPC).

52 Background: Radiotherapy (RT) is a primary modality in the treatment of NPC. However, 30% of patients present with disease recurrence following RT of this radiosensitive tumor. Here, we investigated the molecular and immune profiles associated with radioresistant (RR) NPC. Additionally, we investigated for aberrant molecular pathways in paired recurrences of patients to uncover new drivers underpinning radioresistance. Methods: We prospectively recruited a cohort of 100 NPC patients who completed definitive RT/chemoRT; including 30 cases who were recruited at recurrence. Whole exome sequencing (WES) at 200x was performed to identify low frequencies ( < 1%) of true somatic nucleotide variants (SNVs) and copy number alterations (CNAs). Transcriptomic profiles from RNAseq were interrogated using supervised and unsupervised statistical approaches to determine aberrant pathways that were significantly associated with RR. Results: Genomic instabilityas characterized by percentage genome alteration (PGA) was comparable in our cohort. Additionally, we did not observe any common or exclusive CNAs between RR- and nr-NPC cases. Based on a constellation of immune-related signatures, we observed an “immune-cold” profile that is associated with RR-NPC compared to nr-NPC controls, which is characterized by low expression of CD8+ T cell infiltration and interferon-γ response. Expectedly, pathways relating to angiogenesis, hypoxia and NOTCH signaling were upregulated in the RR-NPC cohort. Interestingly, we observed a reversal of the immune phenotype from “cold” to an enrichment of effector T cell infiltration in the paired recurrences. Conclusions: Here, we present a comprehensive mutational landscape of RR-NPC, which revealed the potential role of the immune environment in modulating RR. The longitudinal immune dysregulation of the tumor microenvironment between the de novo tumors and recurrences could be a driver or passenger event during the onset of recurrence.