Immunometabolic Determinants of Chemoradiotherapy Response and Survival in Head and Neck Squamous Cell Carcinoma
Krupar R, Hautmann MG, Pathak RR, Varier I, Mclaren C, Gaag D, Hellerbrand C, Evert M, Laban S, Idel C, Sandulache V, Perner S, Boßerhoff AK, Sikora AG (2017)
Publication Type: Journal article
Publication year: 2017
Journal
DOI: 10.1016/j.ajpath.2017.09.013
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.
Authors with CRIS profile
Claus Hellerbrand
Professur für Biochemie und Molekulare Pathobiologie
Anja Katrin Boßerhoff
Lehrstuhl für Biochemie und Molekulare Medizin
Involved external institutions
Houston Texas Medical Center
United States (USA) (US)
Universitätsklinikum Schleswig-Holstein (UKSH)
Germany (DE)
Universitätsklinikum Heidelberg
Germany (DE)
Universität Regensburg
Germany (DE)
Tulane University
United States (USA) (US)
Universitätsklinikum Regensburg
Germany (DE)
United States (USA) (US)
Universitätsklinikum Schleswig-Holstein (UKSH)
Germany (DE)
Universitätsklinikum Heidelberg
Germany (DE)
Universität Regensburg
Germany (DE)
Tulane University
United States (USA) (US)
Universitätsklinikum Regensburg
Germany (DE)
How to cite
APA:
Krupar, R., Hautmann, M.G., Pathak, R.R., Varier, I., Mclaren, C., Gaag, D.,... Sikora, A.G. (2017). Immunometabolic Determinants of Chemoradiotherapy Response and Survival in Head and Neck Squamous Cell Carcinoma. American Journal of Pathology. https://dx.doi.org/10.1016/j.ajpath.2017.09.013
MLA:
Krupar, Rosemarie, et al. "Immunometabolic Determinants of Chemoradiotherapy Response and Survival in Head and Neck Squamous Cell Carcinoma." American Journal of Pathology (2017).
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