2. Academic Validation
  3. OSU-T315 overcomes immunosuppression in triple-negative breast cancer by targeting the ILK/NF-κB signaling pathway to enhance immunotherapeutic efficacy

OSU-T315 overcomes immunosuppression in triple-negative breast cancer by targeting the ILK/NF-κB signaling pathway to enhance immunotherapeutic efficacy

  • Int Immunopharmacol. 2024 Dec 25;143(Pt 3):113530. doi: 10.1016/j.intimp.2024.113530.
Yi Wang 1,  Yuenong Qin 2,  Chunyu Wu 2,  Jiajing Chen 2,  Yang Zhang 3,  Yueqiang Chen 4,  Xiaohong Xie 5,  Xiufei Gao 5,  Chenping Sun 6,  Sheng Liu 7
Affiliations

Affiliations

  • 1 Breast Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Zhejiang 310000, China; Integrated Traditional Chinese and Western Medicine Breast Department, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China; Postgraduate School, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2 Integrated Traditional Chinese and Western Medicine Breast Department, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China.
  • 3 Thyroid and Breast Surgery Department, Affiliated Hospital to Shandong University of Traditional Chinese Medicine, Shandong 250000, China.
  • 4 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 5 Breast Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Zhejiang 310000, China.
  • 6 Integrated Traditional Chinese and Western Medicine Breast Department, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China. Electronic address: scplhyy@163.com.
  • 7 Integrated Traditional Chinese and Western Medicine Breast Department, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China; Postgraduate School, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: lhyytcmls@163.com.
PMID: 39515039 DOI: 10.1016/j.intimp.2024.113530
Abstract

Triple negative breast Cancer (TNBC) is an aggressive and immunogenic subtype of breast Cancer. The absence of biomarker has given Immune Checkpoint inhibitors (ICIs) a broad prospect in this type of breast Cancer. The infiltration of regulatory T cells (Tregs) expressing transcription factor forkhead box P3 (Foxp3) in the tumor microenvironment (TME) is the key factor leading to ICIs resistance. Therefore, elimination of tumor antigen-specific Tregs may be an important aspect of improving ICIs efficacy. In this study, it based on the Gene Expression Omnibus and The Cancer Genome Atlas database, along with in vivo and in vitro experimental models, to verified that the high expression of integrin-linked kinase (ILK) in TNBC is the key differential factor leading to the high infiltration of Foxp3+-Tregs in the TME. Then, we selected ILK-specific inhibitor, OSU-T315, to intervene in vitro and vivo. Importantly, we found that OSU-T315 blocked the secretion of CCL17/CCL22 in tumor cells by inhibiting the ILK/NF-κB pathway, resulting in the Apoptosis of Foxp3+-Tregs and decreased programmed cell death-1 (PD-1) expression. Therefore, our findings indicate a novel mechanism of OSU-T315 with potential therapeutic application in TNBC.

Keywords

Integrin-linked kinase; OSU-T315; Programmed cell death-1; T regulatory cells; Triple negative breast cancer.

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