Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany.
Deutsches Zentrum Für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
Cancer Immunol Immunother. 2024 Mar 2;73(4):67. doi: 10.1007/s00262-024-03653-1.
Neutrophils are known to contribute in many aspects of tumor progression and metastasis. The presence of neutrophils or neutrophil-derived mediators in the tumor microenvironment has been associated with poor prognosis in several types of solid tumors. However, the effects of classical cancer treatments such as radiation therapy on neutrophils are poorly understood. Furthermore, the cellular composition and distribution of immune cells in the tumor is of increasing interest in cancer research and new imaging technologies allow to perform more complex spatial analyses within tumor tissues. Therefore, we aim to offer novel insight into intra-tumoral formation of cellular neighborhoods and communities in murine breast cancer. To address this question, we performed image mass cytometry on tumors of the TS/A breast cancer tumor model, performed spatial neighborhood analyses of the tumor microenvironment and quantified neutrophil-extracellular trap degradation products in serum of the mice. We show that irradiation with 2 × 8 Gy significantly alters the cellular composition and spatial organization in the tumor, especially regarding neutrophils and other cells of the myeloid lineage. Locally applied radiotherapy further affects neutrophils in a systemic manner by decreasing the serum neutrophil extracellular trap concentrations which correlates positively with survival. In addition, the intercellular cohesion is maintained due to radiotherapy as shown by E-Cadherin expression. Radiotherapy, therefore, might affect the epithelial-mesenchymal plasticity in tumors and thus prevent metastasis. Our findings underscore the growing importance of the spatial organization of the tumor microenvironment, particularly with respect to radiotherapy, and provide insight into potential mechanisms by which radiotherapy affects epithelial-mesenchymal plasticity and tumor metastasis.
中性粒细胞在肿瘤的发生和转移过程中起着多种作用。在多种实体肿瘤中，肿瘤微环境中存在中性粒细胞或中性粒细胞衍生的介质与预后不良有关。然而，经典癌症治疗方法（如放射疗法）对中性粒细胞的影响还知之甚少。此外，肿瘤中免疫细胞的细胞组成和分布在癌症研究中越来越受到关注，新的成像技术允许在肿瘤组织内进行更复杂的空间分析。因此，我们旨在为研究鼠乳腺癌肿瘤内细胞邻居和社区的形成提供新的视角。为了解决这个问题，我们对 TS/A 乳腺癌肿瘤模型的肿瘤进行了图像质谱细胞分析，对肿瘤微环境进行了空间邻居分析，并定量分析了小鼠血清中的中性粒细胞胞外诱捕网降解产物。我们发现，2×8 Gy 的照射显著改变了肿瘤中的细胞组成和空间组织，特别是中性粒细胞和其他髓系细胞。局部应用的放射疗法通过降低血清中性粒细胞胞外诱捕网浓度进一步以全身性方式影响中性粒细胞，而血清中性粒细胞胞外诱捕网浓度与存活率呈正相关。此外，由于放射疗法，细胞间的凝聚力得以维持，如 E-钙黏蛋白的表达所示。因此，放射疗法可能会影响肿瘤的上皮-间充质可塑性，从而防止转移。我们的研究结果强调了肿瘤微环境空间组织的重要性日益增加，特别是与放射疗法有关，并为放射疗法如何影响上皮-间充质可塑性和肿瘤转移提供了潜在机制的见解。
