PMID- 38422959 OWN - NLM STAT- MEDLINE DCOM- 20240321 LR - 20240321 IS - 1879-0534 (Electronic) IS - 0010-4825 (Linking) VI - 171 DP - 2024 Mar TI - Identification of SLC2A1 as a predictive biomarker for survival and response to immunotherapy in lung squamous cell carcinoma. PG - 108183 LID - S0010-4825(24)00267-1 [pii] LID - 10.1016/j.compbiomed.2024.108183 [doi] AB - BACKGROUND: As one of the common subtypes of non-small lung cancer, lung squamous cell carcinoma (LUSC) patients with advanced stage have few choices of treatment strategies. Therefore, it is urgent to discover genes that are associated with the survival and efficacy of immunotherapies. METHOD: Differential gene expression analyses were conducted using TCGA LUSC bulk-sequencing and single-cell RNA-sequencing data. Prognostic genes were identified from the TCGA LUSC cohort. Protein expression validation and survival analyses were performed. Experiments were conducted to explore the underlying mechanisms. In addition, the correlation between gene expression and pathological response to adjuvant immunochemotherapy was also investigated. RESULTS: After a series of bioinformatic analyses, solute carrier family 2 member 1(SLC2A1), encoding glucose transporter-1 (GLUT1), was found to be differentially expressed between tumor and normal tissues. GLUT1 was subsequently identified as an independent prognostic factor for LUSC. GSEA analysis revealed the glycolysis metabolism pathway of KEGG enriched in SLC2A1(high) tumor tissues. LASSO analyses revealed that tumor tissues with high expression of SLC2A1 were associated with high levels of protein lactylation. We found that SLC2A1 was preferentially expressed by SPP1(+) macrophages in the tumor microenvironment, and the expression of SLC2A1 was associated with the abundance of SPP1(+) macrophages. Immunofluorescence demonstrated GLUT1 and HIF1alpha colocalization in tumor-infiltrating macrophages. In vitro experiments showed HIF-1alpha-induced macrophage polarization under hypoxia, and GLUT1 inhibition blocked this polarization. In addition, SLC2A1 was negatively associated with the common immune checkpoint molecules, such as programmed cell death 1(PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T-lymphocyte associated protein 4 (CTLA4) and lymphocyte activating 3 (LAG3), while showed a positive association with CD44. Finally, we observed that there was a significant correlation between pre-adjuvant-treatment GLUT1 expression and the pathological response. CONCLUSION: SLC2A1 expression was differentially upregulated in tumor tissues, and elevated GLUT1 expression was associated with worse survival and poor pathological response to adjuvant immunochemotherapy. Upregulation of GLUT1 promoted macrophage polarization into the M2 phenotype. The findings will contribute to guiding the treatment selection for LUSC patients and providing personalized immunotherapy strategies. CI - Copyright (c) 2024 Elsevier Ltd. All rights reserved. FAU - Hao, Bo AU - Hao B AD - Department of Thoracic Surgery, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan 430060, China. Electronic address: haobo0528@163.com. FAU - Dong, Huixing AU - Dong H AD - Department of Pulmonary and Critical Care Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai 200336, China. Electronic address: DHX2002@shtrhospital.com. FAU - Xiong, Rui AU - Xiong R AD - Department of Thoracic Surgery, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan 430060, China. Electronic address: 562897392@qq.com. FAU - Song, Congkuan AU - Song C AD - Department of Thoracic Surgery, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan 430060, China. Electronic address: sck2018@whu.edu.cn. FAU - Xu, Chenzhen AU - Xu C AD - Department of Thoracic Surgery, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan 430060, China. Electronic address: xuchenzhen@whu.edu.cn. FAU - Li, Ning AU - Li N AD - Department of Thoracic Surgery, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan 430060, China. Electronic address: md.lining@whu.edu.cn. FAU - Geng, Qing AU - Geng Q AD - Department of Thoracic Surgery, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan 430060, China. Electronic address: gengqingwhu@whu.edu.cn. LA - eng PT - Journal Article DEP - 20240222 PL - United States TA - Comput Biol Med JT - Computers in biology and medicine JID - 1250250 RN - 0 (Glucose Transporter Type 1) RN - 0 (Biomarkers) RN - 0 (SLC2A1 protein, human) SB - IM MH - Humans MH - Glucose Transporter Type 1/genetics MH - *Carcinoma, Non-Small-Cell Lung/genetics/therapy MH - *Lung Neoplasms/genetics/therapy MH - *Carcinoma, Squamous Cell/genetics/therapy MH - Biomarkers MH - Immunotherapy MH - Lung MH - Tumor Microenvironment OTO - NOTNLM OT - GLUT1 OT - Glycolysis OT - Immunotherapy OT - Lung squamous cell carcinoma OT - SLC2A1 COIS- Declaration of competing interest The authors declared that they had no competing interests. EDAT- 2024/03/01 01:22 MHDA- 2024/03/21 12:42 CRDT- 2024/02/29 18:17 PHST- 2023/11/04 00:00 [received] PHST- 2024/01/20 00:00 [revised] PHST- 2024/02/18 00:00 [accepted] PHST- 2024/03/21 12:42 [medline] PHST- 2024/03/01 01:22 [pubmed] PHST- 2024/02/29 18:17 [entrez] AID - S0010-4825(24)00267-1 [pii] AID - 10.1016/j.compbiomed.2024.108183 [doi] PST - ppublish SO - Comput Biol Med. 2024 Mar;171:108183. doi: 10.1016/j.compbiomed.2024.108183. Epub 2024 Feb 22.