Introduction: Chemokine (C-X3-C Motif) Receptor 1 (CX3CR1) is present in a subset of the immune cells in the tumor microenvironment (TME) and plays an essential and diverse role in cancer progression. However, its potential function in the irradiated TME remains unknown. Materials and Methods: A mouse lung cancer model was performed by subcutaneously inoculating Lewis Lung Carcinoma (LLC) cells expressing luciferase (Luc-2) and mCherry cells in CX3CR1GFP/GFP, CX3CR1DTR/+, and wild–type (WT) mice. Bioluminescence imaging, clonogenic assay, and flow cytometry were used to assess tumor progression, proliferation, and cell composition after radiation. Results: Radiation provoked a significant influx of CX3CR1-expressing immune cells, notably monocytes and macrophages, into the TME. Co-culturing irradiated LLC cells with CX3CR1-deficient monocytes, and macrophages resulted in reduced clonogenic survival and increased apoptosis of the cancer cells. Interestingly, deficiency of CX3CR1 in macrophages led to a redistribution of the irradiated LLC cells in the S-phase, parallel to increased expression of cyclin E1, required for cell cycle G1/S transition. In addition, the deficiency of CX3CR1 expression in macrophages altered the cytokine secretion with a decrease in interleukin 6, a crucial mediator of cancer cell survival and proliferation. Next, LLC cells were injected subcutaneously into CX3CR1DTR/+mice, sensitive to diphtheria toxin (DT), and WT mice. After injection, tumors were irradiated with 8 Gy, and mice were treated with DT, leading to conditional ablation of CX3CR1-expressing cells. After three weeks, CX3CR1-depleted mice displayed reduced tumor progression. Furthermore, combining the S-phase-specific chemotherapeutic gemcitabine with CX3CR1 cell ablation resulted in additional attenuation of tumor progression. Conclusions: CX3CR1-expressing mononuclear cells invade the TME after radiation therapy in a mouse lung cancer model. CX3CR1 cell depletion attenuates tumor progression following radiation and sensitizes the tumor to S–phase-specific chemotherapy. Thus, we propose a novel strategy to improve radiation sensitivity by targeting the CX3CR1-expressing immune cells.
引言：趋化因子（C-X3-C基序）受体1（CX3CR1）存在于肿瘤微环境（TME）中的部分免疫细胞内，在癌症进展中发挥关键且多样的作用。然而，其在辐照后TME中的潜在功能尚不明确。材料与方法：通过皮下接种表达荧光素酶（Luc-2）和mCherry的Lewis肺癌（LLC）细胞，在CX3CR1GFP/GFP、CX3CR1DTR/+及野生型（WT）小鼠中建立肺癌模型。采用生物发光成像、克隆形成实验和流式细胞术评估辐照后肿瘤进展、增殖及细胞组成变化。结果：辐照显著诱导表达CX3CR1的免疫细胞（特别是单核细胞和巨噬细胞）向TME浸润。将辐照后的LLC细胞与CX3CR1缺陷型单核细胞及巨噬细胞共培养后，癌细胞克隆存活率降低，凋亡增加。值得注意的是，巨噬细胞中CX3CR1的缺失导致辐照后LLC细胞在S期分布比例改变，同时细胞周期G1/S转换关键调控因子细胞周期蛋白E1表达上调。此外，巨噬细胞CX3CR1表达缺陷会改变细胞因子分泌谱，其中对癌细胞存活和增殖至关重要的白细胞介素6分泌减少。随后，将LLC细胞皮下接种至对白喉毒素（DT）敏感的CX3CR1DTR/+小鼠及WT小鼠中。接种后对肿瘤进行8 Gy辐照，并给予DT处理以条件性清除表达CX3CR1的细胞。三周后，CX3CR1缺失小鼠的肿瘤进展显著减缓。进一步将S期特异性化疗药物吉西他滨与CX3CR1细胞清除联用，可产生协同抑制肿瘤进展的效果。结论：在肺癌小鼠模型中，表达CX3CR1的单核细胞在放疗后浸润TME。清除CX3CR1阳性细胞可抑制放疗后肿瘤进展，并增强肿瘤对S期特异性化疗的敏感性。因此，本研究提出通过靶向表达CX3CR1的免疫细胞来提升放疗敏感性的新策略。
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