Development and validation of a combined hypoxia and immune prognostic classifier for head and neck cancer

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Development and validation of a combined hypoxia and immune prognostic classifier for head and neck cancer. / Brooks, Jill; Antao Mobre De Menezes, Albert Rahul Eugene; Ibrahim, Maha; Archer, Lucinda; Lal, Neeraj; Bagnall, Chris; Zeidler, Sandra Ventorin von; Valentine, Helen; Spruce, Rachel; Batis, Nikolaos; Bryant, Jennifer; Hartley, Margaret; Kaul, Baksho; Ryan, Gordon; Bao, Riyue; Khattri, Arun; Lee, Steve; Ogbureke, Kalu U.E.; Middleton, Gary; Tennant, Daniel; Beggs, Andrew; Deeks, Jon; West, Catharine M L; Cazier, Jean-Baptiste; Willcox, Benjamin; Seiwert, Tanguy Y.; Mehanna, Hisham.

In: Clinical Cancer Research, Vol. 25, No. 17, 09.2019, p. 5315-5328.

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@article{5151296924c6429e9f03985a18d8649e,
title = "Development and validation of a combined hypoxia and immune prognostic classifier for head and neck cancer",
abstract = "Purpose: Intratumoral hypoxia and immunity have been correlated with patient outcome in various tumor 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 on the basis of literature review. Gene expression was analyzed in silico using the The Cancer Genome Atlas (TCGA) HNC dataset (n = 275) and validated using two independent cohorts (n = 130 and 123). IHC 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 intratumoral CD3 protein expression were associated with improved OS on multivariate analysis. Hypoxialow/immunehigh and hypoxiahigh/immunelow tumors were overrepresented in “inflamed” and “immune-desert” microenvironmental profiles, respectively. Multiplex staining demonstrated an inverse correlation between CA-IX expression and prevalence of intratumoral CD3+ T cells (r = −0.5464; P = 0.0377), further corroborating the transcription-based classification.Conclusions: 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.",
author = "Jill Brooks and {Antao Mobre De Menezes}, {Albert Rahul Eugene} and Maha Ibrahim and Lucinda Archer and Neeraj Lal and Chris Bagnall and Zeidler, {Sandra Ventorin von} and Helen Valentine and Rachel Spruce and Nikolaos Batis and Jennifer Bryant and Margaret Hartley and Baksho Kaul and Gordon Ryan and Riyue Bao and Arun Khattri and Steve Lee and Ogbureke, {Kalu U.E.} and Gary Middleton and Daniel Tennant and Andrew Beggs and Jon Deeks and West, {Catharine M L} and Jean-Baptiste Cazier and Benjamin Willcox and Seiwert, {Tanguy Y.} and Hisham Mehanna",
year = "2019",
month = sep,
doi = "10.1158/1078-0432.CCR-18-3314",
language = "English",
volume = "25",
pages = "5315--5328",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research",
number = "17",

}

RIS

TY - JOUR

T1 - Development and validation of a combined hypoxia and immune prognostic classifier for head and neck cancer

AU - Brooks, Jill

AU - Antao Mobre De Menezes, Albert Rahul Eugene

AU - Ibrahim, Maha

AU - Archer, Lucinda

AU - Lal, Neeraj

AU - Bagnall, Chris

AU - Zeidler, Sandra Ventorin von

AU - Valentine, Helen

AU - Spruce, Rachel

AU - Batis, Nikolaos

AU - Bryant, Jennifer

AU - Hartley, Margaret

AU - Kaul, Baksho

AU - Ryan, Gordon

AU - Bao, Riyue

AU - Khattri, Arun

AU - Lee, Steve

AU - Ogbureke, Kalu U.E.

AU - Middleton, Gary

AU - Tennant, Daniel

AU - Beggs, Andrew

AU - Deeks, Jon

AU - West, Catharine M L

AU - Cazier, Jean-Baptiste

AU - Willcox, Benjamin

AU - Seiwert, Tanguy Y.

AU - Mehanna, Hisham

PY - 2019/9

Y1 - 2019/9

N2 - Purpose: Intratumoral hypoxia and immunity have been correlated with patient outcome in various tumor 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 on the basis of literature review. Gene expression was analyzed in silico using the The Cancer Genome Atlas (TCGA) HNC dataset (n = 275) and validated using two independent cohorts (n = 130 and 123). IHC 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 intratumoral CD3 protein expression were associated with improved OS on multivariate analysis. Hypoxialow/immunehigh and hypoxiahigh/immunelow tumors were overrepresented in “inflamed” and “immune-desert” microenvironmental profiles, respectively. Multiplex staining demonstrated an inverse correlation between CA-IX expression and prevalence of intratumoral CD3+ T cells (r = −0.5464; P = 0.0377), further corroborating the transcription-based classification.Conclusions: 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.

AB - Purpose: Intratumoral hypoxia and immunity have been correlated with patient outcome in various tumor 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 on the basis of literature review. Gene expression was analyzed in silico using the The Cancer Genome Atlas (TCGA) HNC dataset (n = 275) and validated using two independent cohorts (n = 130 and 123). IHC 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 intratumoral CD3 protein expression were associated with improved OS on multivariate analysis. Hypoxialow/immunehigh and hypoxiahigh/immunelow tumors were overrepresented in “inflamed” and “immune-desert” microenvironmental profiles, respectively. Multiplex staining demonstrated an inverse correlation between CA-IX expression and prevalence of intratumoral CD3+ T cells (r = −0.5464; P = 0.0377), further corroborating the transcription-based classification.Conclusions: 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.

UR - http://www.scopus.com/inward/record.url?scp=85071788107&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-3314

DO - 10.1158/1078-0432.CCR-18-3314

M3 - Article

VL - 25

SP - 5315

EP - 5328

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 17

ER -