Notwithstanding the well-recognized involvement of chronic neutrophilic inflammation in the initiation phase of many types of epithelial cancers, a growing body of evidence has also implicated these cells in the pathogenesis of the later phases of cancer development, specifically progression and spread. In this setting, established tumors have a propensity to induce myelopoiesis and to recruit neutrophils to the tumor microenvironment (TME), where these cells undergo reprogramming and transitioning to myeloid-derived suppressor cells (MDSCs) with a pro-tumorigenic phenotype. In the TME, these MDSCs, via the production of a broad range of mediators, not only attenuate the anti-tumor activity of tumor-infiltrating lymphocytes, but also exclude these cells from the TME. Realization of the pro-tumorigenic activities of MDSCs of neutrophilic origin has resulted in the development of a range of adjunctive strategies targeting the recruitment of these cells and/or the harmful activities of their mediators of immunosuppression. Most of these are in the pre-clinical or very early clinical stages of evaluation. Notable exceptions, however, are several pharmacologic, allosteric inhibitors of neutrophil/MDSC CXCR1/2 receptors. These agents have entered late-stage clinical assessment as adjuncts to either chemotherapy or inhibitory immune checkpoint-targeted therapy in patients with various types of advanced malignancy. The current review updates the origins and identities of MDSCs of neutrophilic origin and their spectrum of immunosuppressive mediators, as well as current and pipeline MDSC-targeted strategies as potential adjuncts to cancer therapies. These sections are preceded by a consideration of the carcinogenic potential of neutrophils.

中文翻译：

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中性粒细胞在晚期癌症发病机制中的作用和对治疗的反应性受损

尽管众所周知慢性中性粒细胞炎症参与多种类型的上皮癌的起始阶段，但越来越多的证据表明这些细胞与癌症发展后期的发病机制有关，特别是进展和扩散。在这种情况下，已建立的肿瘤倾向于诱导骨髓细胞生成并将中性粒细胞募集到肿瘤微环境 (TME)，在那里这些细胞经历重编程并转变为具有促肿瘤发生表型的髓源性抑制细胞 (MDSC)。在 TME 中，这些 MDSCs 通过产生广泛的介质，不仅减弱肿瘤浸润淋巴细胞的抗肿瘤活性，而且还将这些细胞排除在 TME 之外。中性粒细胞来源的 MDSCs 促肿瘤发生活性的实现导致了一系列辅助策略的发展，这些策略针对这些细胞的募集和/或它们的免疫抑制介质的有害活性。其中大部分处于临床前或非常早期的临床评估阶段。然而，值得注意的例外是中性粒细胞/MDSC CXCR1/2 受体的几种药理学变构抑制剂。这些药物已进入后期临床评估，作为化疗或抑制性免疫检查点靶向治疗的辅助手段，用于治疗各种类型的晚期恶性肿瘤。本综述更新了中性粒细胞来源的 MDSCs 的起源和身份及其免疫抑制介质的谱系，以及当前和管道 MDSC 靶向策略作为癌症治疗的潜在辅助手段。这些部分之前考虑了中性粒细胞的致癌潜力。