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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number111085
JournaliScience
Volume27
Issue number11
DOIs
StatePublished - Nov 15 2024

Keywords

  • Cancer
  • Immunology
  • Molecular biology
  • Neuroscience

ASJC Scopus subject areas

  • General

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