肿瘤和循环中表达 CXCR1/2 的中性粒细胞和 CXCR1/2 配体的水平与患者预后不良相关，与肿瘤淋巴细胞含量呈负相关，并预测免疫检查点抑制剂 (ICI) 治疗失败。因此，CXCR2 选择性和 CXCR1/2 双重抑制剂在小鼠肿瘤模型中作为单一药物以及与 ICI 治疗联合使用均表现出活性。基于这些报告，针对癌症患者的CXCR1/2轴拮抗剂与ICI治疗相结合的临床试验正在进行中。据认为，CXCR1/2 阻断通过阻断中性粒细胞趋化性和减少肿瘤中中性粒细胞含量来影响肿瘤。在这里，我们表明，虽然 CXCR2 拮抗作用确实减缓了肿瘤生长，但它并不排除中性粒细胞募集到肿瘤中。相反，CXCR1/2 抑制通过阻止转录程序向免疫抑制表型的极化并使中性粒细胞无法抑制淋巴细胞增殖来改变中性粒细胞功能。这与活性氧和精氨酸酶 1 释放到细胞外环境的减少有关。值得注意的是，这些疗法不会影响中性粒细胞吞噬和杀死摄入细菌的能力。总而言之，这些结果从机制上解释了为什么 CXCR1/2 抑制在癌症中发挥作用，但没有感染并发症。© 2024 作者。经泰勒许可出版

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.© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.