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

Authors
  • Krupar, Rosemarie1
  • Hautmann, Matthias G2
  • Pathak, Ravi R3
  • Varier, Indu4
  • McLaren, Cassandra3
  • Gaag, Doris5
  • Hellerbrand, Claus6
  • Evert, Matthias5
  • Laban, Simon7
  • Idel, Christian8
  • Sandulache, Vlad3
  • Perner, Sven9
  • Bosserhoff, Anja K6
  • Sikora, Andrew G3
  • 1 Pathology of the University Medical Center Schleswig-Holstein, Campus Lübeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Lübeck, Germany; Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas. Electronic address: [email protected] , (Germany)
  • 2 Department of Radiotherapy, University Hospital Regensburg, Regensburg, Germany. , (Germany)
  • 3 Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas.
  • 4 Department of Pediatrics, Tulane University, New Orleans, Louisiana.
  • 5 Institute of Pathology, University of Regensburg, Regensburg, Germany. , (Germany)
  • 6 Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. , (Germany)
  • 7 Department of Oto-Rhino-Laryngology, Head and Neck Surgery, University Medical Center, Ulm, Germany. , (Germany)
  • 8 Pathology of the University Medical Center Schleswig-Holstein, Campus Lübeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Lübeck, Germany; Department of Otorhinolaryngology, University Hospital Schleswig-Holstein, Lübeck, Germany. , (Germany)
  • 9 Pathology of the University Medical Center Schleswig-Holstein, Campus Lübeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Lübeck, Germany. , (Germany)
Type
Published Article
Journal
American Journal Of Pathology
Publisher
Elsevier
Publication Date
Jan 01, 2018
Volume
188
Issue
1
Pages
72–83
Identifiers
DOI: 10.1016/j.ajpath.2017.09.013
PMID: 29107073
Source
Medline
License
Unknown

Abstract

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.

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