Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), c/o Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy.
Department of Science, Roma Tre University, Rome, Italy.
Cancer Immunol Immunother. 2024 May 2;73(6):113. doi: 10.1007/s00262-024-03695-5.
Senescent cells have a profound impact on the surrounding microenvironment through the secretion of numerous bioactive molecules and inflammatory factors. The induction of therapy-induced senescence by anticancer drugs is known, but how senescent tumor cells influence the tumor immune landscape, particularly neutrophil activity, is still unclear. In this study, we investigate the induction of cellular senescence in breast cancer cells and the subsequent immunomodulatory effects on neutrophils using the CDK4/6 inhibitor palbociclib, which is approved for the treatment of breast cancer and is under intense investigation for additional malignancies. Our research demonstrates that palbociclib induces a reversible form of senescence endowed with an inflammatory secretome capable of recruiting and activating neutrophils, in part through the action of interleukin-8 and acute-phase serum amyloid A1. The activation of neutrophils is accompanied by the release of neutrophil extracellular trap and the phagocytic removal of senescent tumor cells. These findings may be relevant for the success of cancer therapy as neutrophils, and neutrophil-driven inflammation can differently affect tumor progression. Our results reveal that neutrophils, as already demonstrated for macrophages and natural killer cells, can be recruited and engaged by senescent tumor cells to participate in their clearance. Understanding the interplay between senescent cells and neutrophils may lead to innovative strategies to cope with chronic or tumor-associated inflammation.
衰老细胞通过分泌大量生物活性分子和炎症因子，对周围的微环境产生深远的影响。抗癌药物诱导的治疗性衰老已被证实，但是衰老肿瘤细胞如何影响肿瘤免疫景观，特别是中性粒细胞的活性，目前仍不清楚。在这项研究中，我们使用已被批准用于乳腺癌治疗的 CDK4/6 抑制剂帕博西尼（palbociclib），研究其诱导乳腺癌细胞衰老以及随后对中性粒细胞的免疫调节作用。帕博西尼还在针对其他恶性肿瘤进行深入研究。我们的研究表明，帕博西尼诱导的衰老具有一种可逆转的形式，其炎症分泌组能够招募和激活中性粒细胞，部分是通过白细胞介素-8 和急性期血清淀粉样蛋白 A1 的作用。中性粒细胞的激活伴随着中性粒细胞细胞外诱捕网的释放和衰老肿瘤细胞的吞噬清除。这些发现可能与癌症治疗的成功有关，因为中性粒细胞和中性粒细胞驱动的炎症可以不同地影响肿瘤进展。我们的结果表明，中性粒细胞可以像巨噬细胞和自然杀伤细胞一样被衰老的肿瘤细胞招募和激活，参与其清除过程。了解衰老细胞和中性粒细胞之间的相互作用可能会为应对慢性或与肿瘤相关的炎症带来新的策略。
