Institute of Pulmonary Medicine, Hadassah Medical Center, Jerusalem 91120, Israel.
Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Cells. 2022 Feb 23;11(5):783. doi: 10.3390/cells11050783.
Immunotherapy has become a leading modality for the treatment of cancer, but despite its increasing success, a substantial number of patients do not benefit from it. Cancer-related neutrophils have become, in recent years, a subject of growing interest. Distinct sub-populations of neutrophils have been identified at advanced stages of cancer. In this study, we aimed to evaluate the role of neutrophils in mediating the efficacy of immune checkpoint inhibitors (ICI) treatments (α-PD-1/PD-L1), by assessing lung tumor models in mice. We found that G-CSF overexpression by the tumor significantly potentiates the efficacy of ICI, whereas neutrophils' depletion abrogated their responses. Adoptive transfer of circulating normal-density neutrophils (NDN) resulted in significantly reduced tumor growth, whereas low-density neutrophils (LDN) had no effect. We next investigated the effect of ICI on neutrophils' functions. Following α-PD-L1 treatment, NDN displayed increased ROS production and increased cytotoxicity toward tumor cells but decreased degranulation. Together, our results suggest that neutrophils are important mediators of the ICI treatments and that mainly NDN are modulated following α-PD-L1 treatment. This research provides a better understanding of the function of neutrophils following immunotherapies and their impact on the efficacy of immunotherapy, supporting better understanding and future improvement of currently available treatments.
免疫疗法已成为癌症治疗的主要手段，但尽管其成功率不断提高，仍有相当数量的患者无法从中受益。近年来，癌症相关的中性粒细胞已成为研究热点。在癌症的晚期阶段，已经确定了不同的中性粒细胞亚群。在这项研究中，我们旨在通过评估小鼠肺肿瘤模型来评估中性粒细胞在介导免疫检查点抑制剂（ICI）治疗（α-PD-1/PD-L1）疗效中的作用。我们发现肿瘤中 G-CSF 的过表达显著增强了 ICI 的疗效，而中性粒细胞的耗竭则消除了它们的反应。循环正常密度中性粒细胞（NDN）的过继转移导致肿瘤生长明显减少，而低密度中性粒细胞（LDN）则没有影响。接下来，我们研究了 ICI 对中性粒细胞功能的影响。在用 α-PD-L1 治疗后，NDN 显示出增加的 ROS 产生和对肿瘤细胞的增加的细胞毒性，但脱颗粒减少。综上所述，我们的研究结果表明，中性粒细胞是 ICI 治疗的重要介导者，并且主要是 NDN 在 α-PD-L1 治疗后被调节。这项研究为免疫治疗后中性粒细胞的功能及其对免疫治疗疗效的影响提供了更好的理解，支持了对现有治疗方法的更好理解和未来改进。
