The Crosstalk with CXCL10‐Rich Tumor‐Associated Mast Cells Fuels Pancreatic Cancer Progression and Immune Escape
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, necessitating approaches to improve prognosis. As the mediator of allergic process, mast cells have been found in various cancers and are associated with survival. However, the biological behaviors of tumor-associated mast cells (TAMCs) remain unclear. Herein, an excessive infiltration of TAMCs in PDAC is demonstrated, which apparently associated with poor survival in PDAC patients. PDAC cells are found to recruit CXCR2<sup>+</sup> MCs into TME, and then inhibited MCs ferroptosis, and maintained their proliferation. Concomitantly, the tumor-derived exosome miR-188-5p activated the PTEN/AKT/GSK3β signaling, further stabilized transcriptional factor ERG by inhibiting its ubiquitin degradation, and finally enhanced the transcription of cxcl10 within TAMCs. In reverse, TAMCs-derived CXCL10 reversely promoted tumor epithelial-mesenchymal transition and induced immunosuppressive tumor microenvironment by recruiting CXCR3<sup>+</sup> Tregs. Sodium cromoglycate (SCG) is a membrane stabilizer for MCs and confirmed as an effective and widely used agent to block TAMCs-derived CXCL10 and further sensitize the therapeutic efficacy of anti-PD-1 antibody plus gemcitabine for PDAC. These findings illuminate a critical and innovative crosstalk between TAMCs and PDAC cells that promote PDAC progression, and SCG sensitizes PDAC to the current immuno-chemotherapy, which reveals its potential to be a valuable adjuvant for PDAC patients.
Authors
- Huaxiang Xu (ORCID: https://orcid.org/0000-0002-5346-2335)
- Sami Shoucair
- Shanshan Gao
- Hanlin Yin (ORCID: https://orcid.org/0000-0002-6622-4301)
- Wenhui Lou (ORCID: https://orcid.org/0000-0001-5820-6843)
- Qiangda Chen (ORCID: https://orcid.org/0000-0003-0428-5173)
- Taochen He
- Joseph R. Habib (ORCID: https://orcid.org/0000-0003-3445-2278)
- Ning Pu (ORCID: https://orcid.org/0000-0002-3123-493X)
- Chenye Shi (ORCID: https://orcid.org/0000-0001-6800-1649)
- Wenquan Wang (ORCID: https://orcid.org/0000-0002-4696-8098)
- Junyi He (ORCID: https://orcid.org/0009-0004-1558-1511)
- Michael Goggins (ORCID: https://orcid.org/0000-0002-4286-2296)
- Wenchuan Wu (ORCID: https://orcid.org/0000-0002-5020-5165)
- Liang Liu (ORCID: https://orcid.org/0000-0001-8630-7430)
- Juan Wang (ORCID: https://orcid.org/0000-0002-2537-1348)
- Yuqi Xie (ORCID: https://orcid.org/0000-0002-8764-5842)
- Lei Zhang (ORCID: https://orcid.org/0000-0003-1215-6486)
- Jun Yu (ORCID: https://orcid.org/0009-0003-2523-7258)
- Yun Jin (ORCID: https://orcid.org/0000-0001-7750-1370)
- Wei Gan (ORCID: https://orcid.org/0000-0003-2795-8289)
Institutions
- Kunming University of Science and Technology (CN)
- Johns Hopkins University (US)
- Sun Yat-sen University (CN)
- Fudan University (CN)
- Johns Hopkins Medicine (US)
- Tianjin Medical University Cancer Institute and Hospital (CN)
- NYU Langone Health (US)
- First People's Hospital of Yunnan Province (CN)
- Zhongshan Hospital (CN)
- Cancer Research Center (US)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-02-18
- DOI
- https://doi.org/10.1002/advs.202417724
- Citations
- 13
- Primary Topic
- Mast cells and histamine
- Type
- article
- Field-Weighted Citation Impact
- 10.37
Funders
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Program of Shanghai Academic Research Leader