Tumor-infiltrating mast cells confer resistance to immunotherapy in pancreatic cancer

Ying Ma; Xiangqin Zhao; Jingyan Feng; Suimin Qiu; Baoan Ji; Lu Huang; Patrick Hwu; Craig D Logsdon; Huamin Wang

doi:10.1016/j.isci.2024.111085

Tumor-infiltrating mast cells confer resistance to immunotherapy in pancreatic cancer

iScience. 2024 Sep 30;27(11):111085. doi: 10.1016/j.isci.2024.111085. eCollection 2024 Nov 15.

Authors

Ying Ma^{1

2

3}, Xiangqin Zhao¹, Jingyan Feng⁴, Suimin Qiu⁵, Baoan Ji⁶, Lu Huang², Patrick Hwu^{2

7}, Craig D Logsdon^{8

9}, Huamin Wang^{10

11}

Affiliations

¹ Department 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.
² Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
³ Department of Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁴ Seekgene Biotechnology Co, Ltd, Beijing 102200, China.
⁵ Department of Surgical Pathology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
⁶ Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
⁷ Moffitt Cancer Center, Tampa, FL 33612, USA.
⁸ Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁹ Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
¹⁰ Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
¹¹ The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.

Abstract

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.

Keywords: Cancer; Immunology; Molecular biology; Neuroscience.