Improving Stereotactic Body Radiation Therapy by Rewiring Immunosuppressive Neutrophils in Murine Pancreatic Ductal Adenocarcinoma

Joseph D Murphy; Gary Hannon; Bradley N Mills; Angela L Hughson; Taylor P Uccello; Nicholas W Gavras; Jian Ye; Brian A Belt; Maggie L Lesch; Sarah L Eckl; Elena B Barr; Edith M Lord; Minsoo Kim; Haoming Qiu; David C Linehan; Scott A Gerber

doi:10.1016/j.ijrobp.2025.06.3853

Improving Stereotactic Body Radiation Therapy by Rewiring Immunosuppressive Neutrophils in Murine Pancreatic Ductal Adenocarcinoma

Int J Radiat Oncol Biol Phys. 2025 Jul 1:S0360-3016(25)04495-5. doi: 10.1016/j.ijrobp.2025.06.3853. Online ahead of print.

Authors

Affiliations

¹ Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York.
² Department of Surgery, University of Rochester Medical Center, Rochester, New York.
³ Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York.
⁴ Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York; Department of Surgery, University of Rochester Medical Center, Rochester, New York. Electronic address: Scott_gerber@urmc.rochester.edu.

PMID: 40609840
DOI: 10.1016/j.ijrobp.2025.06.3853

Abstract

Purpose: Deciphering the role of neutrophils to radiation response in pancreatic ductal adenocarcinoma (PDAC).

Methods: Using a murine model of PDAC, mice were treated with a clinically- relevant regime of targeted stereotactic body radiation therapy (SBRT). Neutrophil infiltration and activation status were assessed by flow cytometry and immunohistochemistry. Depletion studies were used to determine their role in overall treatment response. Finally, microspheres containing IL-12 cytokine were employed following SBRT to therapeutically repolarize these cells.

Results: Following SBRT, neutrophils infiltrated PDAC tumors in high numbers and largely exhibited an immunosuppressive phenotype. Depletion studies confirmed their role in acquired radioresistance, as SBRT efficacy was improved in their absence. Delivering IL-12 cytokine following SBRT could repolarize these cells to be immunostimulatory and enhance anti-tumor immunity in this model.

Conclusion: Neutrophils are key players in SBRT and IL-12 treatment and can act as a double-edged sword depending on the treatment employed.

Abstract

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