Nonclassical action of Ku70 promotes Treg-suppressive function through a FOXP3-dependent mechanism in lung adenocarcinoma
Ku70, a DNA repair protein, binds to the damaged DNA ends and orchestrates the recruitment of other proteins to facilitate repair of DNA double-strand breaks. Besides its essential role in DNA repair, several studies have highlighted nonclassical functions of Ku70 in cellular processes. However, its function in immune homeostasis and antitumor immunity remains unknown. Here, we discovered a marked association between elevated Ku70 expression and unfavorable prognosis in lung adenocarcinoma, focusing specifically on increased Ku70 levels in tumor-infiltrated Tregs. Using a lung-colonizing tumor model in mice with Treg-specific Ku70 deficiency, we demonstrated that deletion of Ku70 in Tregs led to a stronger antitumor response and slower tumor growth due to impaired immune-suppressive capacity of Tregs. Furthermore, we confirmed that Ku70 played a critical role in sustaining the suppressive function of human Tregs. We found that Ku70 bound to forkhead box protein P3 (FOXP3) and occupied FOXP3-bound genomic sites to support its transcriptional activities. These findings not only unveil a nonhomologous end joining-independent (NHEJ-independent) role of Ku70 crucial for Treg-suppressive function, but also underscore the potential of targeting Ku70 as an effective strategy in cancer therapy, aiming to both restrain cancer cells and enhance pulmonary antitumor immunity.
Authors
- Youqiong Ye (ORCID: https://orcid.org/0000-0001-8332-4710)
- Jianfeng Zhang (ORCID: https://orcid.org/0000-0003-1686-9010)
- Shengming Dai (ORCID: https://orcid.org/0000-0001-7398-3165)
- Xueyu Dai (ORCID: https://orcid.org/0000-0001-5406-5940)
- Bin Li
- Dan Li (ORCID: https://orcid.org/0000-0002-4831-5103)
- Chuan Wang (ORCID: https://orcid.org/0000-0003-3079-8431)
- Na Tian (ORCID: https://orcid.org/0000-0003-2526-8911)
- Yanhua Du
- Wenle Zhang
- Hao Cheng (ORCID: https://orcid.org/0000-0002-5091-3874)
- Qianjun Zhou
- Rui Liang (ORCID: https://orcid.org/0009-0004-6748-5142)
- Shiyang Song
- Qianru Huang
- Xinnan Liu
- Zhi Chen (ORCID: https://orcid.org/0009-0000-5387-8376)
Institutions
- Shanghai Jiao Tong University (CN)
- Anhui Medical University (CN)
- Renji Hospital (CN)
- Ruijin Hospital (CN)
- Shanghai Chest Hospital (CN)
- University of Gdańsk (PL)
- Shanghai University of Traditional Chinese Medicine (CN)
- Longhua Hospital Shanghai University of Traditional Chinese Medicine (CN)
- Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine (CN)
- Shanghai Pulmonary Hospital (CN)
- Peking University Shenzhen Hospital (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Shanghai Sixth People's Hospital (CN)
- Shanghai Skin Disease Hospital (CN)
- Gdańsk Medical University (PL)
- University of Oulu (FI)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-10-24
- DOI
- https://doi.org/10.1172/jci178079
- Citations
- 4
- Primary Topic
- Cancer-related molecular mechanisms research
- Type
- article
- Field-Weighted Citation Impact
- 1.14
Funders
- Shanghai Municipal Education Commission
- National Key Research and Development Program of China