ADAM9 drives the immunosuppressive microenvironment by cholesterol biosynthesis-mediated activation of IL6-STAT3 signaling for lung tumor progression

Jing-Pei Liu; Kuan-Yin Shen; Wei-Chung Cheng; Wei-Chao Chang; Chih-Ying Hsieh; Chia-Chien Lo; Ting-Ting Kuo; Ching-Chan Lin; Shih-Jen Liu; Wen-Chin Huang; Yuh-Pyng Sher

doi:10.62347/LODV2387

ADAM9 drives the immunosuppressive microenvironment by cholesterol biosynthesis-mediated activation of IL6-STAT3 signaling for lung tumor progression

Am J Cancer Res. 2024 Apr 15;14(4):1850-1865. doi: 10.62347/LODV2387. eCollection 2024.

Authors

Jing-Pei Liu¹, Kuan-Yin Shen², Wei-Chung Cheng³, Wei-Chao Chang⁴, Chih-Ying Hsieh⁵, Chia-Chien Lo⁴, Ting-Ting Kuo⁶, Ching-Chan Lin⁵, Shih-Jen Liu⁷, Wen-Chin Huang^{1

8

9}, Yuh-Pyng Sher^{1

3

4

6

9

10}

Affiliations

¹ Graduate Institute of Biomedical Sciences, China Medical University Taichung 404, Taiwan.
² School of Dentistry, Tri-Service General Hospital and National Defense Medical Center Taipei 114, Taiwan.
³ The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica Taichung 404, Taiwan.
⁴ Center for Molecular Medicine, China Medical University Hospital Taichung 404, Taiwan.
⁵ Division of Hematology and Oncology, China Medical University Hospital Taichung 404, Taiwan.
⁶ Institute of Biochemistry and Molecular Biology, China Medical University Taichung 404, Taiwan.
⁷ National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes Miaoli 350, Taiwan.
⁸ Graduate Institute of Cell Biology, China Medical University Taichung 404, Taiwan.
⁹ The International Master's Program of Biomedical Sciences, China Medical University Taichung 404, Taiwan.
¹⁰ Cancer Biology and Precision Therapeutics Center, China Medical University Taichung 404, Taiwan.

Abstract

Chronic inflammation associated with lung cancers contributes to immunosuppressive tumor microenvironments, reducing CD8⁺ T-cell function and leading to poor patient outcomes. A disintegrin and metalloprotease domain 9 (ADAM9) promotes cancer progression. Here, we aim to elucidate the role of ADAM9 in the immunosuppressive tumor microenvironment. A bioinformatic analysis of TIMER2.0 was used to investigate the correlation of ADAM9 and to infiltrate immune cells in the human lung cancer database and mouse lung tumor samples. Flow cytometry, immunohistochemistry, and RNA sequencing (RNA-seq) were performed to investigate the ADAM9-mediated immunosuppressive microenvironment. The coculture system of lung cancer cells with immune cells, cytokine array assays, and proteomic approach was used to investigate the mechanism. By analyzing the human LUAD database and the mouse lung cancer models, we showed that ADAM9 was associated with the immunosuppressive microenvironment. Additionally, ADAM9 released IL6 protein from cancer cells to inhibit IL12p40 secretion from dendritic cells, therefore leading to dendritic cell dysfunction and further affecting T-cell functions. Proteomic analysis indicated that ADAM9 promoted cholesterol biosynthesis and increased IL6-STAT3 signaling. Mechanistically, ADAM9 reduced the protein stability of LDLR, resulting in reduced cholesterol uptake and induced cholesterol biosynthesis. Moreover, LDLR reduction enhanced IL6-STAT3 activation. We reveal that ADAM9 has a novel biological function that drives the immunosuppressive tumor microenvironment by linking lung cancer's metabolic and signaling axes. Thus, by targeting ADAM9 an innovative and promising therapeutic opportunity was indicated for regulating the immunosuppression of lung cancer.

Keywords: ADAM9; IL6; STAT3; cholesterol; immune suppression.