CXCR1/2 antagonism inhibits neutrophil function and not recruitment in cancer.

Autor:	Kwak JW; Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, USA., Nguyen HQ; Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, USA., Camai A; Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, USA., Huffman GM; Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, USA., Mekvanich S; Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, USA., Kenney NN; Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, USA., Zhu X; Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, USA., Randolph TW; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, USA., Houghton AM; Translational Science & Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, USA.; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, USA.; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.; Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle, WA, USA.
Jazyk:	angličtina
Zdroj:	Oncoimmunology [Oncoimmunology] 2024 Jul 26; Vol. 13 (1), pp. 2384674. Date of Electronic Publication: 2024 Jul 26 (Print Publication: 2024).
DOI:	10.1080/2162402X.2024.2384674
Abstrakt:	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. Competing Interests: No potential conflict of interest was reported by the author(s). (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)
Databáze:	MEDLINE
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