Obesity accelerates immune evasion of non-small cell lung carcinoma via TFEB-dependent upregulation of Siglec-15 and glycolytic reprogramming. (1st December 2022)

• Record Type: Journal Article
• Authors: Zhang, Cai; Zhou, Lijie; Li, Songyang; Zhao, Junwei; Meng, Xianchun; Ma, Liwei; Wang, Yongfeng; Li, Cai; Zheng, Lu; Ming, Liang
• Is Part Of: Cancer letters. Volume 550(2022)
• Publication Date: 2022-12-01
• Subjects: Obesity -- Non-small cell lung carcinoma -- TFEB -- Immune evasion -- Immune checkpoint blockade; CLEAR the coordinated lysosomal expression and regulation -- CTLA-4 cytotoxic T lymphocyte-associated antigen-4 -- CTLs cytotoxic CD8+ T lymphocytes -- DIO diet-induced obesity -- GzmB granzyme B -- HFD high-fat diet -- HK2 hexokinase 2 -- ICB immune checkpoint blockade -- LDHA lactate dehydrogenase A -- NSCLC non-small cell lung cancer -- PD-1 programmed cell death protein-1 -- PD-L1 programmed death ligand-1 -- Siglec-15 sialic acid binding Ig-like lectin 15 -- TCM tumor-conditioned medium -- TFEB transcription factor EB -- TME tumor microenvironment; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.215918
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Although obesity contributes to tumor incidence and progression in various cancers, whether obesity impacts the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC) remains largely under-explored. We generated NSCLC xenograft model in diet-induced obese mice and identified that TFEB is critical to accelerate obesity-related NSCLC progression with mimic intrinsic functions on tumor biology. Mechanically, TFEB binds directly to Siglec-15 promoter to upregulate Siglec-15 expression and binds to Hk2 and Ldha promoters to enhance glycolytic flux in NSCLC cells, which restrain the expansion and cytotoxic function of CD8 + T cells while maintain suppressive Treg cells in TME, jointly promoting immune evasion of NSCLC cells in obesity. Blocking tumor TFEB improves the therapeutic efficiency of anti-PD-1 in obese mice. Altogether, our data identify essential roles of TFEB in remodeling immunosuppressive TME and promoting NSCLC development in obesity, providing scientific rational for TFEB as a potential biomarker to predict immune checkpoint blockade efficiency in obese NSCLC patients. Highlights: Obesity promotes non-small cell lung cancer (NSCLC) progression. Obesity induces TFEB in NSCLC cells to suppress cytotoxic CD8 + T cells through upregulating Siglec-15. Obesity induces TFEB to boost glycolytic flux in NSCLC cells to support the suppressive phenotype of Treg cells. TFEB silencing enhances NSCLC cells response to anti-PD-1 immunotherapy in obesity.