Multimodal analysis suggests differential immuno-metabolic crosstalk in lung squamous cell carcinoma and adenocarcinoma

Leitner B.P. Givechian K.B. Ospanova S. Beisenbayeva A. Politi K. Perry R.J.
December 2022 Nature Research

npj Precision Oncology
2022 #6 Issue 1

Immunometabolism within the tumor microenvironment is an appealing target for precision therapy approaches in lung cancer. Interestingly, obesity confers an improved response to immune checkpoint inhibition in non-small cell lung cancer (NSCLC), suggesting intriguing relationships between systemic metabolism and the immunometabolic environment in lung tumors. We hypothesized that visceral fat and ¹⁸F-Fluorodeoxyglucose uptake influenced the tumor immunometabolic environment and that these bidirectional relationships differ in NSCLC subtypes, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). By integrating ¹⁸F-FDG PET/CT imaging, bulk and single-cell RNA-sequencing, and histology, we observed that LUSC had a greater dependence on glucose than LUAD. In LUAD tumors with high glucose uptake, glutaminase was downregulated, suggesting a tradeoff between glucose and glutamine metabolism, while in LUSC tumors with high glucose uptake, genes related to fatty acid and amino acid metabolism were also increased. We found that tumor-infiltrating T cells had the highest expression of glutaminase, ribosomal protein 37, and cystathionine gamma-lyase in NSCLC, highlighting the metabolic flexibility of this cell type. Further, we demonstrate that visceral adiposity, but not body mass index (BMI), was positively associated with tumor glucose uptake in LUAD and that patients with high BMI had favorable prognostic transcriptional profiles, while tumors of patients with high visceral fat had poor prognostic gene expression. We posit that metabolic adjunct therapy may be more successful in LUSC rather than LUAD due to LUAD’s metabolic flexibility and that visceral adiposity, not BMI alone, should be considered when developing precision medicine approaches for the treatment of NSCLC.

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Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, United States
Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven, CT, United States
Department of Genetics, Yale School of Medicine, New Haven, CT, United States
Nazarbayev Intellectual School of Physics and Mathematics, Almaty, Kazakhstan
Kazakhstan International School, Almaty, Kazakhstan
Department of Pathology, Yale School of Medicine, New Haven, CT, United States
Department of Internal Medicine (Oncology), Yale School of Medicine, New Haven, CT, United States
Yale Cancer Center, Yale School of Medicine, New Haven, CT, United States

Department of Cellular & Molecular Physiology
Department of Internal Medicine (Endocrinology)
Department of Genetics
Nazarbayev Intellectual School of Physics and Mathematics
Kazakhstan International School
Department of Pathology
Department of Internal Medicine (Oncology)
Yale Cancer Center

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