Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
Department of Radiation Oncology, University Hospital of North Norway, Tromsø, Norway.
Front Immunol. 2024 Sep 6;15:1433237. doi: 10.3389/fimmu.2024.1433237. eCollection 2024.
Cancer-associated fibroblasts (CAFs) are abundant and influential elements of the tumor microenvironment (TME), giving support to tumor development in multiple ways. Among other mechanisms, CAFs are important regulators of immunological processes occurring in tumors. However, CAF-mediated tumor immunomodulation in the context of radiotherapy remains poorly understood. In this study, we explore effects of radiation on CAF-derived immunoregulatory signals to the TME.
Primary CAF cultures were established from freshly collected human NSCLC lung tumors. CAFs were exposed to single-high or fractionated radiation regimens (1x18Gy or 3x6Gy), and the expression of different immunoregulatory cell-associated and secreted signaling molecules was analyzed 48h and 6 days after initiation of treatment. Analyses included quantitative measurements of released damage-associated molecular patterns (DAMPs), interferon (IFN) type I responses, expression of immune regulatory receptors, and secretion of soluble cytokines, chemokines, and growth factors. CAFs are able to survive ablative radiation regimens, however they enter into a stage of premature cell senescence.
Our data show that CAFs avoid apoptosis and do not contribute by release of DAMPs or IFN-I secretion to radiation-mediated tumor immunoregulation. Furthermore, the secretion of relevant immunoregulatory cytokines and growth factors including TGF-β, IL-6, IL-10, TNFα, IL-1β, VEGF, CXCL12, and CXCL10 remain comparable between non-irradiated and radiation-induced senescent CAFs. Importantly, radiation exposure modifies the cell surface expression of some key immunoregulatory receptors, including upregulation of CD73 and CD276.
Our data suggest that CAFs do not participate in the release of danger signals or IFN-I secretion following radiotherapy. The immune phenotype of CAFs and radiation-induced senescent CAFs is similar, however, the observed elevation of some cell surface immunological receptors on irradiated CAFs could contribute to the establishment of an enhanced immunosuppressive TME after radiotherapy.
癌症相关成纤维细胞（CAFs）是肿瘤微环境（TME）中丰富且具有影响力的成分，通过多种方式为肿瘤的发展提供支持。除其他机制外，CAFs 是肿瘤中发生的免疫过程的重要调节剂。然而，CAF 介导的放疗中的肿瘤免疫调节在很大程度上仍不清楚。在这项研究中，我们探讨了辐射对 CAF 衍生的免疫调节信号对 TME 的影响。
从新鲜收集的人非小细胞肺癌肺肿瘤中建立原代 CAF 培养物。CAF 暴露于单次高剂量或分次辐射方案（1x18Gy 或 3x6Gy），并在治疗开始后 48 小时和 6 天分析不同免疫调节细胞相关和分泌的信号分子的表达。分析包括释放的损伤相关分子模式（DAMPs）的定量测量、I 型干扰素（IFN）反应、免疫调节受体的表达以及可溶性细胞因子、趋化因子和生长因子的分泌。CAF 能够存活消融辐射方案，但它们进入过早细胞衰老的阶段。
我们的数据表明，CAF 避免凋亡，并且不会通过释放 DAMPs 或 IFN-I 分泌来促进辐射介导的肿瘤免疫调节。此外，包括 TGF-β、IL-6、IL-10、TNFα、IL-1β、VEGF、CXCL12 和 CXCL10 在内的相关免疫调节细胞因子和生长因子的分泌在未照射和辐射诱导的衰老 CAF 之间保持相当。重要的是，辐射暴露改变了一些关键免疫调节受体的细胞表面表达，包括 CD73 和 CD276 的上调。
我们的数据表明，CAF 不会在放疗后释放危险信号或 IFN-I 分泌。CAF 的免疫表型与辐射诱导的衰老 CAF 相似，然而，在照射的 CAF 上观察到一些细胞表面免疫受体的升高可能有助于在放疗后建立增强的免疫抑制 TME。
