Immunometabolic Determinants of Chemoradiotherapy Response and Survival in Head and Neck Squamous Cell Carcinoma

Tumor immune microenvironment and tumor metabolism are major determinants of chemoradiotherapy response. The interdependency and prognostic significance of specific immune and metabolic phenotypes in head and neck squamous cell carcinoma (HNSCC) were assessed and changes in reactive oxygen species w...

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Bibliographic Details
Published in:	The American journal of pathology Vol. 188; no. 1; pp. 72 - 83
Main Authors:	Krupar, Rosemarie, Hautmann, Matthias G., Pathak, Ravi R., Varier, Indu, McLaren, Cassandra, Gaag, Doris, Hellerbrand, Claus, Evert, Matthias, Laban, Simon, Idel, Christian, Sandulache, Vlad, Perner, Sven, Bosserhoff, Anja K., Sikora, Andrew G.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-01-2018
Subjects:	Aged Antineoplastic Agents - therapeutic use Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - mortality Carcinoma, Squamous Cell - therapy CD8 Antigens - genetics CD8 Antigens - metabolism Cell Line, Tumor Chemoradiotherapy Cytochrome c Group - genetics Cytochrome c Group - metabolism Databases, Genetic Female Glucose Transporter Type 1 - genetics Glucose Transporter Type 1 - metabolism Head and Neck Neoplasms - metabolism Head and Neck Neoplasms - mortality Head and Neck Neoplasms - therapy Humans Male Middle Aged Prognosis Reactive Oxygen Species - metabolism Survival Rate
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Summary:	Tumor immune microenvironment and tumor metabolism are major determinants of chemoradiotherapy response. The interdependency and prognostic significance of specific immune and metabolic phenotypes in head and neck squamous cell carcinoma (HNSCC) were assessed and changes in reactive oxygen species were evaluated as a mechanism of treatment response in tumor spheroid/immunocyte co-cultures. Pretreatment tumor biopsies were immunohistochemically characterized in 73 HNSCC patients treated by definitive chemoradiotherapy and correlated with survival. The prognostic significance of CD8A, GLUT1, and COX5B gene expression was analyzed within The Cancer Genome Atlas database. HNSCC spheroids were co-cultured in vitro with peripheral blood mononuclear cells (PBMCs) in the presence of the glycolysis inhibitor 2-deoxyglucose and radiation treatment followed by PBMC chemotaxis determination via fluorescence microscopy. In the chemoradiotherapy-treated HNSCC cohort, mitochondrial-rich (COX5B) metabolism correlated with increased and glucose-dependent (GLUT1) metabolism with decreased intratumoral CD8/CD4 ratios. High CD8/CD4, together with mitochondrial-rich or glucose-independent metabolism, was associated with improved short-term survival. The Cancer Genome Atlas analysis confirmed that patients with a favorable immune and metabolic gene signature (high CD8A, high COX5B, low GLUT1) had improved short- and long-term survival. In vitro, 2-deoxyglucose and radiation synergistically up-regulated reactive oxygen species–dependent PBMC chemotaxis to HNSCC spheroids. These results suggest that glucose-independent tumor metabolism is associated with CD8-dominant antitumor immune infiltrate, and together, these contribute to improved chemoradiotherapy response in HNSCC.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0002-9440 1525-2191
DOI:	10.1016/j.ajpath.2017.09.013