Immuno-metabolic determinants of chemoradiotherapy response and survival in head and neck squamous cell carcinoma.

Immuno-metabolic determinants of chemoradiotherapy response and survival in head and neck squamous cell carcinoma.

Am J Pathol. 2017 Oct 26;:

Authors: 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

Abstract
Tumor immune microenvironment and tumor metabolism are major determinants of chemoradiotherapy response. We assessed the interdependency and prognostic significance of specific immune and metabolic phenotypes in head and neck squamous cell carcinoma (HNSCC) and evaluated changes in reactive oxygen species as a mechanism of treatment response in tumor spheroid/immunocyte co-cultures. Pretreatment tumor biopsies were immunohistochemically characterized in a cohort of 73 HNSCC patients treated by definitive chemoradiotherapy and correlated with survival. The prognostic significance of CD8A, GLUT1, and COX5B gene expression were analyzed within The Cancer Genome Atlas database. HNSCC spheroids were co-cultured in vitro with peripheral blood mononuclear cells (PBMC) 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. Our results suggest that glucose-independent tumor metabolism is associated with CD8-dominant anti-tumor immune infiltrate, and together these contribute to improved chemoradiotherapy response in HNSCC.

PMID: 29107073 [PubMed - as supplied by publisher]

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