Department of Otorhinolaryngology, LMU München, Munich, Germany.
Walter Brendel Centre of Experimental Medicine, LMU München, Munich, Germany.
J Immunother Cancer. 2021 Dec;9(12). doi: 10.1136/jitc-2021-003495.
Beyond their fundamental role in homeostasis and host defense, neutrophilic granulocytes (neutrophils) are increasingly recognized to contribute to the pathogenesis of malignant tumors. Recently, aging of mature neutrophils in the systemic circulation has been identified to be critical for these immune cells to properly unfold their homeostatic and anti-infectious functional properties. The role of neutrophil aging in cancer remains largely obscure.
Employing advanced in vivo microscopy techniques in different animal models of cancer as well as utilizing pulse-labeling and cell transfer approaches, various / assays, and human data, we sought to define the functional relevance of neutrophil aging in cancer.
Here, we show that signals released during early tumor growth accelerate biological aging of circulating neutrophils, hence uncoupling biological from chronological aging of these immune cells. This facilitates the accumulation of highly reactive neutrophils in malignant lesions and endows them with potent protumorigenic functions, thus promoting tumor progression. Counteracting uncoupled biological aging of circulating neutrophils by blocking the chemokine receptor CXCR2 effectively suppressed tumor growth.
Our data uncover a self-sustaining mechanism of malignant neoplasms in fostering protumorigenic phenotypic and functional changes in circulating neutrophils. Interference with this aberrant process might therefore provide a novel, already pharmacologically targetable strategy for cancer immunotherapy.
除了在体内平衡和宿主防御方面的基本作用外，嗜中性粒细胞（中性粒细胞）也越来越被认为有助于恶性肿瘤的发病机制。最近，在系统循环中成熟中性粒细胞的衰老被确定为这些免疫细胞正确发挥其体内平衡和抗感染功能特性的关键。中性粒细胞衰老在癌症中的作用在很大程度上仍然不清楚。
在不同的癌症动物模型中采用先进的体内显微镜技术，以及利用脉冲标记和细胞转移方法、各种测定方法和人类数据，我们试图确定中性粒细胞衰老在癌症中的功能相关性。
在这里，我们表明，早期肿瘤生长过程中释放的信号会加速循环中性粒细胞的生物衰老，从而使这些免疫细胞的生物衰老与时间衰老脱钩。这促进了高反应性中性粒细胞在恶性病变中的积累，并赋予它们强大的促肿瘤功能，从而促进肿瘤的进展。通过阻断趋化因子受体 CXCR2 来阻止循环中性粒细胞的非耦联生物衰老，有效地抑制了肿瘤的生长。
我们的数据揭示了恶性肿瘤的一种自我维持机制，促进了循环中性粒细胞中促肿瘤表型和功能的变化。因此，干扰这种异常过程可能为癌症免疫治疗提供一种新的、已经具有药理学靶向性的策略。
