Tumor-infiltrating mast cells confer resistance to immunotherapy in pancreatic cancer
Summary: Pancreatic ductal adenocarcinoma (PDAC) exhibits an immunosuppressive tumor microenvironment (TME) contributing to its therapeutic resistance. Following our previous studies, we report that mast cells infiltrating the PDAC TME foster this immunosuppression and desmoplasia. Mast cell infiltr...
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Elsevier
2024-11-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224023101 |
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| author | Ying Ma Xiangqin Zhao Jingyan Feng Suimin Qiu Baoan Ji Lu Huang Patrick Hwu Craig D. Logsdon Huamin Wang |
| author_facet | Ying Ma Xiangqin Zhao Jingyan Feng Suimin Qiu Baoan Ji Lu Huang Patrick Hwu Craig D. Logsdon Huamin Wang |
| author_sort | Ying Ma |
| collection | DOAJ |
| description | Summary: Pancreatic ductal adenocarcinoma (PDAC) exhibits an immunosuppressive tumor microenvironment (TME) contributing to its therapeutic resistance. Following our previous studies, we report that mast cells infiltrating the PDAC TME foster this immunosuppression and desmoplasia. Mast cell infiltration correlated with human PDAC progression, and genetic or pharmacological mast cell depletion reduced tumor growth and desmoplasia while enhancing survival in mouse PDAC models. Mechanistically, mast cell-derived IL-10 promoted PDAC progression. Strikingly, combining an agonistic anti-OX40 immunotherapy with mast cell blockade synergistically elicited durable anti-tumor immunity, marked by increased infiltration of CD8+ T effector cells expressing granzyme B and dramatic survival benefit unachievable with either approach alone. An OX40-associated gene signature correlated with improved survival in human PDAC, supporting therapeutic translation. Our findings establish mast cells as promoters of the suppressive PDAC TME and rational targets for combination immunotherapy. Targeting this mast cell-mediated resistance mechanism could overcome immunotherapy failure in PDAC. |
| format | Article |
| id | doaj-art-8ba0ca18fc4549e4be9de91c49b16a3d |
| institution | OA Journals |
| issn | 2589-0042 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-8ba0ca18fc4549e4be9de91c49b16a3d2025-08-20T01:47:51ZengElsevieriScience2589-00422024-11-01271111108510.1016/j.isci.2024.111085Tumor-infiltrating mast cells confer resistance to immunotherapy in pancreatic cancerYing Ma0Xiangqin Zhao1Jingyan Feng2Suimin Qiu3Baoan Ji4Lu Huang5Patrick Hwu6Craig D. Logsdon7Huamin Wang8Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China; Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Corresponding authorDepartment of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, ChinaSeekgene Biotechnology Co, Ltd, Beijing 102200, ChinaDepartment of Surgical Pathology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USADepartment of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USAMelanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USAMelanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Moffitt Cancer Center, Tampa, FL 33612, USADepartment of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USADepartment of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USASummary: Pancreatic ductal adenocarcinoma (PDAC) exhibits an immunosuppressive tumor microenvironment (TME) contributing to its therapeutic resistance. Following our previous studies, we report that mast cells infiltrating the PDAC TME foster this immunosuppression and desmoplasia. Mast cell infiltration correlated with human PDAC progression, and genetic or pharmacological mast cell depletion reduced tumor growth and desmoplasia while enhancing survival in mouse PDAC models. Mechanistically, mast cell-derived IL-10 promoted PDAC progression. Strikingly, combining an agonistic anti-OX40 immunotherapy with mast cell blockade synergistically elicited durable anti-tumor immunity, marked by increased infiltration of CD8+ T effector cells expressing granzyme B and dramatic survival benefit unachievable with either approach alone. An OX40-associated gene signature correlated with improved survival in human PDAC, supporting therapeutic translation. Our findings establish mast cells as promoters of the suppressive PDAC TME and rational targets for combination immunotherapy. Targeting this mast cell-mediated resistance mechanism could overcome immunotherapy failure in PDAC.http://www.sciencedirect.com/science/article/pii/S2589004224023101Molecular biologyNeuroscienceImmunologyCancer |
| spellingShingle | Ying Ma Xiangqin Zhao Jingyan Feng Suimin Qiu Baoan Ji Lu Huang Patrick Hwu Craig D. Logsdon Huamin Wang Tumor-infiltrating mast cells confer resistance to immunotherapy in pancreatic cancer iScience Molecular biology Neuroscience Immunology Cancer |
| title | Tumor-infiltrating mast cells confer resistance to immunotherapy in pancreatic cancer |
| title_full | Tumor-infiltrating mast cells confer resistance to immunotherapy in pancreatic cancer |
| title_fullStr | Tumor-infiltrating mast cells confer resistance to immunotherapy in pancreatic cancer |
| title_full_unstemmed | Tumor-infiltrating mast cells confer resistance to immunotherapy in pancreatic cancer |
| title_short | Tumor-infiltrating mast cells confer resistance to immunotherapy in pancreatic cancer |
| title_sort | tumor infiltrating mast cells confer resistance to immunotherapy in pancreatic cancer |
| topic | Molecular biology Neuroscience Immunology Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224023101 |
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