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Abstract
The metabolic properties of tumor microenvironment (TME) are dynamically dysregulated to achieve immune escape and promote cancer cell survival. However, in vivo properties of glucose metabolism in cancer and immune cells are poorly understood and their clinical application to development of a biomarker reflecting immune functionality is still lacking. Methods: We analyzed RNA-seq and fluorodeoxyglucose (FDG) positron emission tomography profiles of 63 lung squamous cell carcinoma (LUSC) specimens to correlate FDG uptake, expression of glucose transporters (GLUT) by RNA-seq and immune cell enrichment score (ImmuneScore). Single cell RNA-seq analysis in five lung cancer specimens was performed. We tested the GLUT3/GLUT1 ratio, the GLUT-ratio, as a surrogate representing immune metabolic functionality by investigating the association with immunotherapy response in two melanoma cohorts. Results: ImmuneScore showed a negative correlation with GLUT1 (r = -0.70, p < 0.01) and a positive correlation with GLUT3 (r = 0.39, p < 0.01) in LUSC. Single-cell RNA-seq showed GLUT1 and GLUT3 were mostly expressed in cancer and immune cells, respectively. In immune-poor LUSC, FDG uptake was positively correlated with GLUT1 (r = 0.27, p = 0.04) and negatively correlated with ImmuneScore (r = -0.28, p = 0.04). In immune-rich LUSC, FDG uptake was positively correlated with both GLUT3 (r = 0.78, p = 0.01) and ImmuneScore (r = 0.58, p = 0.10). The GLUT-ratio was higher in anti-PD1 responders than nonresponders (p = 0.08 for baseline; p = 0.02 for on-treatment) and associated with a progression-free survival in melanoma patients who treated with anti-CTLA4 (p = 0.04). Conclusions: Competitive uptake of glucose by cancer and immune cells in TME could be mediated by differential GLUT expression in these cells.

Affiliations

Kwon Joong Na  1 , Hongyoon Choi  2 , Ho Rim Oh  3   4 , Yoon Ho Kim  3 , Sae Bom Lee  3 , Yoo Jin Jung  3 , Jaemoon Koh  5 , Samina Park  1 , Hyun Joo Lee  1 , Yoon Kyung Jeon  5 , Doo Hyun Chung  5 , Jin Chul Paeng  2 , In Kyu Park  1 , Chang Hyun Kang  1 , Gi Jeong Cheon  2   3 , Keon Wook Kang  2   3 , Dong Soo Lee  2 , Young Tae Kim  1   3
1 Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul, Republic of Korea.
2 Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
3 Seoul National University Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
4 Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
5 Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea.