Purpose: Intratumoural hypoxia and immunity have been correlated with patient outcome in various tumour settings. However, these factors are not currently considered for treatment selection in head and neck cancer (HNC) due to lack of validated biomarkers. Here we sought to develop a hypoxia-immune classifier with potential application in patient prognostication and prediction of response to targeted therapy. Experimental design: A 54-gene hypoxia-immune signature was constructed based on literature review. Gene expression was analysed in silico using the TCGA HNC dataset (n=275) and validated using two independent cohorts (n=130 and 123). Immunohistochemistry was used to investigate the utility of a simplified protein signature. The spatial distribution of hypoxia and immune markers was examined using multiplex immunofluorescence staining. Results: Unsupervised hierarchical clustering of TCGA dataset (development cohort) identified three patient subgroups with distinct hypoxia-immune phenotypes and survival profiles: hypoxialow/immunehigh, hypoxiahigh/immunelow and mixed, with 5-year overall survival (OS) rates of 71%, 51% and 49% respectively (p=0.0015). The prognostic relevance of the hypoxia-immune gene signature was replicated in two independent validation cohorts. Only PD-L1 and intratumoural CD3 protein expression were associated with improved OS on multivariate analysis. Hypoxialow/immunehigh and hypoxiahigh/immunelow tumours were over-represented in 'inflamed' and 'immune-desert' microenvironmental profiles respectively. Multiplex staining demonstrated an inverse correlation between CA-IX expression and prevalence of intratumoural CD3+ T cells (r=-0.5464, p=0.0377), further corroborating the transcription-based classification. Conclusion: We developed and validated a hypoxia-immune prognostic transcriptional classifier, which may have clinical application to guide the use of hypoxia modification and targeted immunotherapies for the treatment of HNC.
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