Year: 2026
Type: article
Abstract: Although the role of neutrophils in modulating antitumor T-cell responses has been extensively studied, their direct effects on tumor cells remain less well understood. In this study, we investigated whether neutrophils have the capacity to directly kill tumor cells independently of T cells. We found that anti-CD40-based therapy, when combined with IL10 receptor blockade, initiates a Batf3-dependent pathway in which IL12 and IFNγ secretion results in oncolytic neutrophil activity. Using a combination of microscopy, single-cell, and functional assays, we observed that killing of tumor cells by neutrophils is dependent on physical contact and degranulation. This degranulation-mediated killing is associated with an atypical dynamic invasive neutrophil phenotype. In line with our preclinical findings, our phase I trial of anti-CD40 shows that circulating IL12, IFNγ, and IL10 increase in response to anti-CD40, whereas our phase Ib/2 PRINCE study shows that lower circulating IL10 is associated with favorable overall survival (OS) specifically among anti-CD40-treated patients. Finally, we found that neutrophil expansion with granulocyte colony-stimulating factor is associated with improved OS, specifically in patients treated with anti-CD40, suggesting that this pathway may be amenable to therapeutic intervention in patients with advanced cancer.
Source: Cancer Immunology Research
Authors: Danny N. Khalil, Ricardo Gomez, Amit Regev, Fadi Samaan, Yacine Marouf, Sadna Budhu, Daniel Hirschhorn, Isabell Schulze, Jessica A. Lavery, Nicholas Ceglia, Samuel S. Freeman, Vivien I. Maltez, Jaynia M. Garcia, Nathan Suek, Chien-Huan Weng, Christopher R. Cabanski, Sébastien Monette, Yevgeniy Romin, Yanyun Li, Ronan Chaligne, Michael J. Yellin, Tibor Keler, Deena M. Maurer, Anne-Laure Flamar, Lucia Morgado-Palacin, Levi M. Mangarin, James J. Harding, Wungki Park, Jaclyn P. Lyman, Stephen Maddock, Mark H. O’Hara, Ghassan K. Abou-Alfa, Robert H. Vonderheide, Eileen M. O’Reilly, Ronald N. Germain, Jedd D. Wolchok, Taha Merghoub
Institutions: Memorial Sloan Kettering Cancer Center, Cornell University, Swim Across America, Weill Cornell Medicine, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Parker Institute for Cancer Immunotherapy, Rockefeller University, Celldex Therapeutics (United States), Lustgarten Foundation, Abramson Cancer Center, University of Pennsylvania, Trinity College Dublin
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: American Association for Cancer Research, American Philosophical Society, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Memorial Sloan-Kettering Cancer Center, Ludwig Institute for Cancer Research, Parker Institute for Cancer Immunotherapy, Swim Across America, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, NHLBI Division of Intramural Research
OpenAlex ID: W7119158992
FWCI:
Cites:
Cited by:
Related to: