Obesity accelerates immune evasion of non-small cell lung carcinoma via TFEB-dependent upregulation of Siglec-15 and glycolytic reprogramming

  • Cancer Lett. 2022 Sep 20;550:215918. doi: 10.1016/j.canlet.2022.215918.
Cai Zhang  1 ,  Lijie Zhou  2 ,  Songyang Li  3 ,  Junwei Zhao  1 ,  Xianchun Meng  1 ,  Liwei Ma  1 ,  Yongfeng Wang  1 ,  Cai Li  3 ,  Lu Zheng  4 ,  Liang Ming  5
Affiliations
  • 1. Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Key Clinical Laboratory of Henan Province, Zhengzhou, 450052, China.
  • 2. Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • 3. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • 4. Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 5. Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Key Clinical Laboratory of Henan Province, Zhengzhou, 450052, China. Electronic address: [email protected].
PMID: 36150633 DOI: 10.1016/j.canlet.2022.215918
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.

Keywords
Immune checkpoint blockade; Immune evasion; Non-small cell lung carcinoma; Obesity; TFEB.
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