Tumor-Derived Factors Differentially Affect the Recruitment and Plasticity of Neutrophils.
Tumor-Derived Factors Differentially Affect the Recruitment and Plasticity of Neutrophils.
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DOI：
10.3390/cancers13205082
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发表时间：
2021-10-11
期刊：
影响因子：
5.2
通讯作者：
Fridlender ZG
中科院分区：
文献类型：
--
作者：
Arpinati L;Kaisar-Iluz N;Shaul ME;Groth C;Umansky V;Fridlender ZG
中性粒细胞是最丰富的循环白细胞类型，在肿瘤生物学中发挥着重要作用。在癌症方面，肿瘤相关中性粒细胞 (TAN) 的起源以及循环中性粒细胞亚群（NDN 和 LDN）之间的相互作用仍不清楚。我们的结果首次表明，TAN 可以起源于 NDN 和 LDN，且 LDN 的渗透程度高于 NDN。 CXCL1 和 CXCL2 趋化因子强烈影响 NDN 和 LDN 迁移，肿瘤条件培养基不同程度地影响它们的趋化性。此外，NDN 显示出肿瘤诱导的表型可塑性，向低密度状态 (LD-NDN) 转变。我们发现肿瘤条件培养基和 CXCL1 促进 LD-NDN 形成，表明多种因素介导中性粒细胞的可塑性。新形成的LD-NDN在形态、功能活性和表面受体表达方面表现出与LDN相似的特征，表明LDN的一部分可能源自经历表型变化的NDN。中性粒细胞在癌症生物学中发挥着关键作用。与循环正常密度中性粒细胞（NDN）相比，低密度中性粒细胞（LDN）的数量随着肿瘤进展而显着增加。这些中性粒细胞亚群与瘤内中性粒细胞 (TAN) 之间的相关性仍存在争议。使用 4T1（乳腺癌）和 AB12（间皮瘤）肿瘤模型，我们旨在阐明 TAN 的来源并评估驱动中性粒细胞在癌症中可塑性的机制。发现 NDN 和 LDN 都会响应 CXCL1 和 CXCL2 暴露而迁移，并在离体和体内共同渗透肿瘤部位，尽管 LDN 向肿瘤的迁移率高于 NDN。肿瘤衍生因子和趋化因子，特别是 CXCL1，被发现可驱动中性粒细胞表型可塑性，诱导 NDN 向低密度状态 (LD-NDN) 转变。 LD-NDN 似乎与 NDN 不同，在核形态、表面受体标记、吞噬能力降低和 ROS 产生增加方面表现出与 LDN 相似的表型特征。有趣的是，所有三个亚群都对肿瘤细胞表现出相当的细胞毒能力。我们的数据表明，TAN 起源于 LDN 和 NDN，并且 LDN 的一部分源自经历表型变化的 NDN。 NDN 可塑性导致表面标记表达和功能活性的变化，获得 LDN 的特征。
Neutrophils are the most abundant type of circulating leukocytes and play an important role in tumor biology. In the context of cancer, the origin of tumor-associated neutrophils (TANs) as well as the interplay between circulating neutrophil subpopulations (NDN and LDN) are still not clear. Our results show for the first time that TANs can originate from both NDN and LDN, with LDN infiltrating at a higher extent than NDN. CXCL1 and CXCL2 chemokines strongly affect NDN and LDN migration, and tumor-conditioned media differently impact their chemotaxis. Moreover, NDN display tumor-induced phenotypical plasticity, transitioning towards a low-density state (LD-NDN). We found that tumor-conditioned media and CXCL1 promote LD-NDN formation, suggesting that multiple factors mediate neutrophils’ plasticity. Newly formed LD-NDN present similar characteristics to LDN in terms of morphology, functional activity, and surface receptor expression, indicating that a portion of LDN could originate from NDN undergoing phenotypical changes. Neutrophils play a key role in cancer biology. In contrast to circulating normal-density neutrophils (NDN), the amount of low-density neutrophils (LDN) significantly increases with tumor progression. The correlation between these neutrophil subpopulations and intratumoral neutrophils (TANs) is still under debate. Using 4T1 (breast) and AB12 (mesothelioma) tumor models, we aimed to elucidate the source of TANs and to assess the mechanisms driving neutrophils’ plasticity in cancer. Both NDN and LDN were found to migrate in response to CXCL1 and CXCL2 exposure, and co-infiltrate the tumor site ex vivo and in vivo, although LDN migration into the tumor was higher than NDN. Tumor-derived factors and chemokines, particularly CXCL1, were found to drive neutrophil phenotypical plasticity, inducing NDN to transition towards a low-density state (LD-NDN). LD-NDN appeared to differ from NDN by displaying a phenotypical profile similar to LDN in terms of nuclear morphology, surface receptor markers, decreased phagocytic abilities, and increased ROS production. Interestingly, all three subpopulations displayed comparable cytotoxic abilities towards tumor cells. Our data suggest that TANs originate from both LDN and NDN, and that a portion of LDN derives from NDN undergoing phenotypical changes. NDN plasticity resulted in a change in surface marker expression and functional activity, gaining characteristics of LDN.
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