Krupar, Rosemarie and Hautmann, Matthias G. and Pathak, Ravi R. and Varier, Indu and McLaren, Cassandra and Gaag, Doris and Hellerbrand, Claus and Evert, Matthias and Laban, Simon and Idel, Christian and Sandulache, Vlad and Perner, Sven and Bosserhoff, Anja K. and Sikora, Andrew G. (2018) Immunometabolic Determinants of Chemoradiotherapy Response and Survival in Head and Neck Squamous Cell Carcinoma. AMERICAN JOURNAL OF PATHOLOGY, 188 (1). pp. 72-83. ISSN 0002-9440, 1525-2191
Full text not available from this repository. (Request a copy)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 mitochondrialrich 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUMOR-INFILTRATING LYMPHOCYTES; CD8(+) T-CELLS; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; RECTAL-CANCER; BREAST-CANCER; RADIATION; LACTATE; GLUCOSE-TRANSPORTER-1; 2-DEOXY-D-GLUCOSE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Strahlentherapie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Mar 2020 06:07 |
| Last Modified: | 23 Mar 2020 06:07 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15480 |
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