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A 26-gene hypoxia signature predicts benefit from hypoxia-modifying therapy in laryngeal cancer but not bladder cancer.

ABSTRACT: Tumor hypoxia is associated with a poor prognosis, hypoxia modification improves outcome, and hypoxic status predicts benefit from treatment. Yet, there is no universal measure of clinical hypoxia. The aim of this study was to investigate whether a 26-gene hypoxia signature predicted benefit from hypoxia-modifying treatment in both cancer types.Samples were available from 157 T2-T4 laryngeal cancer and 185 T1-T4a bladder cancer patients enrolled on the accelerated radiotherapy with carbogen and nicotinamide (ARCON) and bladder carbogen nicotinamide (BCON) phase III randomized trials of radiotherapy alone or with carbogen and nicotinamide (CON) respectively. Customized TaqMan low density arrays (TLDA) were used to assess expression of the 26-gene signature using quantitative real-time PCR. The median expression of the 26 genes was used to derive a hypoxia score (HS). Patients were categorized as TLDA-HS low (?median) or TLDA-HS high (>median). The primary outcome measures were regional control (RC; ARCON) and overall survival (BCON).Laryngeal tumors categorized as TLDA-HS high showed greater benefit from ARCON than TLDA-HS low tumors. Five-year RC was 81% (radiotherapy alone) versus 100% (CON) for TLDA-HS high (P=0.009). For TLDA-HS low, 5-year RC was 91% (radiotherapy alone) versus 90% (CON; P=0.90). TLDA-HS did not predict benefit from CON in bladder cancer.The 26-gene hypoxia signature predicts benefit from hypoxia-modifying treatment in laryngeal cancer. These findings will be evaluated in a prospective clinical trial.

SUBMITTER: Eustace A

PROVIDER: S-EPMC3797516 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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A 26-gene hypoxia signature predicts benefit from hypoxia-modifying therapy in laryngeal cancer but not bladder cancer.

Eustace Amanda A Mani Navin N Span Paul N PN Irlam Joely J JJ Taylor Janet J Betts Guy N J GN Denley Helen H Miller Crispin J CJ Homer Jarrod J JJ Rojas Ana M AM Hoskin Peter J PJ Buffa Francesca M FM Harris Adrian L AL Kaanders Johannes H A M JH West Catharine M L CM

Clinical cancer research : an official journal of the American Association for Cancer Research 20130702 17

<h4>Purpose</h4>Tumor hypoxia is associated with a poor prognosis, hypoxia modification improves outcome, and hypoxic status predicts benefit from treatment. Yet, there is no universal measure of clinical hypoxia. The aim of this study was to investigate whether a 26-gene hypoxia signature predicted benefit from hypoxia-modifying treatment in both cancer types.<h4>Experimental design</h4>Samples were available from 157 T2-T4 laryngeal cancer and 185 T1-T4a bladder cancer patients enrolled on the ...[more]

PMID: 23820108

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Project description:BackgroundIncreasing evidence suggests that the CXC chemokine receptor 6 (CXCR6) is involved in tumor progression and the regulation of tumor immunity. However, its role in muscle-invasive bladder cancer (MIBC) remains largely unexplored.MethodsData from 391 MIBC patients in the TCGA, 212 patients from GEO, 131 patients from our center, 195 patients in the IMvigor210 cohort, and single-cell RNA sequencing (scRNA-seq) data from 9 bladder cancer patients (GSE222315) were analyzed. Additionally, data from the GEPIA 2, TISCH2, TIMER2.0, and UALCAN platforms were utilized to investigate the prognostic and immunotherapeutic significance of CXCR6 in MIBC.ResultsWe observed that CXCR6 expression was significantly reduced in bladder cancer tumors and correlated with tumor stage and grade. Low CXCR6 expression was associated with poor recurrence-free survival (RFS) and overall survival (OS) in the TCGA cohort, a finding validated in both the meta-GEO dataset and our center's cohort. Multivariate analysis confirmed that low CXCR6 expression was an independent predictor of poor OS and RFS. A nomogram incorporating CXCR6 expression and other independent prognostic factors was developed to accurately predict 3- and 5-year OS. Gene set enrichment analysis indicated that immune activation-related pathways were significantly enriched in tumors with high CXCR6 expression. CIBERSORT analysis revealed that CXCR6 expression was positively correlated with CD8+ T cells, CD4+ T cells, activated NK cells, M1 macrophages, and activated dendritic cells in TCGA, findings further validated by TIMER2.0. scRNA-seq data showed that CXCR6 was predominantly expressed in T and NK cells and facilitated T/NK-myeloid interaction via the CXCR6-CXCL16 axis. Importantly, CXCL16+ macrophages and dendritic cells recruited CXCR6+ T and NK cells, which exhibited enhanced cytotoxicity, thereby amplifying anti-tumor immunity. Clinically, in the IMvigor210 immunotherapy cohort, higher CXCR6 expression was associated with improved anti-PD-L1 therapeutic outcomes.ConclusionOur findings highlight CXCR6 as a critical biomarker for predicting prognosis and immunotherapeutic response in MIBC.

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A 26-gene hypoxia signature predicts benefit from hypoxia-modifying therapy in laryngeal cancer but not bladder cancer.

Publications

A 26-gene hypoxia signature predicts benefit from hypoxia-modifying therapy in laryngeal cancer but not bladder cancer.

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