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Updated: Jun 18, 2025
Isolation and Characterization of Neutrophils with Anti-Tumor Properties
Published on: June 19, 2015
CXCR1/2 antagonism inhibits neutrophil function and not recruitment in cancer
Jeff W Kwak1, Helena Q Nguyen1, Alex Camai1
1Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, USA.
Abstract:
The level of tumor and circulating CXCR1/2-expressing neutrophils and CXCR1/2 ligands correlate with poor patient outcomes, inversely correlate with tumoral lymphocyte content, and predict immune checkpoint inhibitor (ICI) treatment failure. Accordingly, CXCR2-selective and CXCR1/2 dual inhibitors exhibit activity both as single agents and in combination with ICI treatment in mouse tumor models. Based on such reports, clinical trials combining CXCR1/2 axis antagonists with ICI treatment for cancer patients are underway. It has been assumed that CXCR1/2 blockade impacts tumors by blocking neutrophil chemotaxis and reducing neutrophil content in tumors. Here, we show that while CXCR2 antagonism does slow tumor growth, it does not preclude neutrophil recruitment into tumor. Instead, CXCR1/2 inhibition alters neutrophil function by blocking the polarization of transcriptional programs toward immune suppressive phenotypes and rendering neutrophils incapable of suppressing lymphocyte proliferation. This is associated with decreased release of reactive oxygen species and Arginase-1 into the extracellular milieu. Remarkably, these therapeutics do not impact the ability of neutrophils to phagocytose and kill ingested bacteria. Taken together, these results mechanistically explain why CXCR1/2 inhibition has been active in cancer but without infectious complications.
Insights
Blocking CXCR1/2 in cancer therapy hinders neutrophil immune suppression, not recruitment. This approach enhances anti-tumor immunity without increasing infection risk, offering a novel therapeutic strategy.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Neutrophils expressing CXCR1/2 and their ligands are linked to poor cancer patient outcomes and predict immune checkpoint inhibitor (ICI) treatment failure.
- CXCR1/2 antagonists show promise in preclinical models, both alone and with ICI therapy, leading to ongoing clinical trials.
Purpose of the Study:
- To elucidate the mechanism by which CXCR1/2 inhibition impacts tumor immunity and neutrophil function.
- To determine if CXCR1/2 blockade affects neutrophil recruitment, function, and potential for infectious complications.
Main Methods:
- Investigated the effects of CXCR2 antagonism on tumor growth and neutrophil infiltration in mouse models.
- Analyzed changes in neutrophil transcriptional programs, immune suppressive functions, and reactive oxygen species/Arginase-1 release.
- Assessed the impact of CXCR1/2 inhibition on neutrophil phagocytosis and bacterial killing capacity.
Main Results:
- CXCR2 antagonism slowed tumor growth but did not prevent neutrophil infiltration into tumors.
- CXCR1/2 inhibition reprogrammed neutrophils, reducing their ability to suppress lymphocyte proliferation.
- Key suppressive molecules like reactive oxygen species and Arginase-1 were decreased, while bacterial killing ability remained intact.
Conclusions:
- CXCR1/2 inhibition enhances anti-tumor immunity by altering neutrophil function, not by reducing neutrophil numbers.
- This mechanism explains the efficacy of CXCR1/2 antagonists in cancer therapy without causing opportunistic infections.
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