IL10R Inhibition Induces Neutrophil Tumoricidal Activity

While the role of neutrophils in modulating antitumor T cell responses has been extensively studied, their direct effects on tumor cells remains 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 interleukin 10 (IL-10) receptor blockade initiates a Batf3-dependent pathway in which IL-12 and interferon gamma (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 1 trial of anti-CD40 shows that circulating IL-12, IFNγ, and IL-10 increase in response to anti-CD40, while our phase 1b/2 PRINCE study shows that lower circulating IL-10 is associated with favorable overall survival specifically among anti-CD40-treated patients. Finally, we found that neutrophil expansion with granulocyte colony stimulating factor (G-CSF) is associated with improved overall survival, specifically in patients treated with anti-CD40, suggesting that this pathway may be amenable to therapeutic intervention in patients with advanced cancer.

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Publication Details

Journal
Cancer Immunology Research
Published
2026-01-07
DOI
https://doi.org/10.1158/2326-6066.cir-25-0834
Primary Topic
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

IL10R Inhibition Induces Neutrophil Tumoricidal Activity

Vivien I. Maltez, Yevgeniy Romin, W. Park, Levi Mangarin et al.
Cancer Immunology Research
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
article

IL10R Inhibition Induces Neutrophil Tumoricidal Activity

Vivien I. Maltez, Yevgeniy Romin, W. Park, Levi Mangarin, Danny Nejad Khalil, J. Harding, Isabell Schulze, Robert H. Vonderheide, Daniel Hirschhorn, Nicholas Ceglia, Amit Regev, R Gómez, Jaclyn P. Lyman, Christopher R. Cabanski, Jedd D. Wolchok, Deena M. Maurer, Samuel S. Freeman, Fadi Samaan, G.K. Abou-Alfa, Sébastien Monette, Lucia Morgado-Palacin, Michael Yellin, Eileen Mary O'Reilly, Sadna Budhu, Nathan Suek, Jessica A. Lavery, Ronald N. Germain, Yacine Marouf, Ronan Chaligné, Tibor Keler, Anne-Laure Flamar, Mark H. O'Hara, Chien-Huan Weng, Jaynia M. Garcia, Stephen Maddock, Taha Merghoub, Yanyun Li
article en

Abstract

While the role of neutrophils in modulating antitumor T cell responses has been extensively studied, their direct effects on tumor cells remains 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 interleukin 10 (IL-10) receptor blockade initiates a Batf3-dependent pathway in which IL-12 and interferon gamma (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 1 trial of anti-CD40 shows that circulating IL-12, IFNγ, and IL-10 increase in response to anti-CD40, while our phase 1b/2 PRINCE study shows that lower circulating IL-10 is associated with favorable overall survival specifically among anti-CD40-treated patients. Finally, we found that neutrophil expansion with granulocyte colony stimulating factor (G-CSF) is associated with improved overall survival, specifically in patients treated with anti-CD40, suggesting that this pathway may be amenable to therapeutic intervention in patients with advanced cancer.

Cancer Immunology Research
Memorial Sloan Kettering Cancer Center (US), Trinity College Dublin (IE), Cornell University (US), Lustgarten Foundation (US), Swim Across America (US), Kettering University (US), Parker Institute for Cancer Immunotherapy (US), National Institute of Allergy and Infectious Diseases (US), Celldex Therapeutics (United States) (US), University of Pennsylvania (US), Rockefeller University (US)
American Association for Cancer Research, 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
Good health and well-being
Openalex Percentile: Top 94%
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
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