免疫原性低分割放射治疗以髓系来源抑制细胞（MDSC）依赖的方式增强头颈部鳞状细胞癌对 PD-L1 治疗的敏感性。
Immunogenic hypofractionated radiotherapy sensitising head and neck squamous cell carcinoma to anti-PD-L1 therapy in MDSC-dependent manner.
机构信息
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 430079, Wuhan, China.
Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, 430079, Wuhan, China.
出版信息
Br J Cancer. 2023 Jun;128(11):2126-2139. doi: 10.1038/s41416-023-02230-0. Epub 2023 Mar 28.
BACKGROUND
Enhancing the response rate of immunotherapy will aid in the success of cancer treatment. Here, we aimed to explore the combined effect of immunogenic radiotherapy with anti-PD-L1 treatment in immunotherapy-resistant HNSCC mouse models.
METHODS
The SCC7 and 4MOSC2 cell lines were irradiated in vitro. SCC7-bearing mice were treated with hypofractionated or single-dose radiotherapy followed by anti-PD-L1 therapy. The myeloid-derived suppressive cells (MDSCs) were depleted using an anti-Gr-1 antibody. Human samples were collected to evaluate the immune cell populations and ICD markers.
RESULTS
Irradiation increased the release of immunogenic cell death (ICD) markers (calreticulin, HMGB1 and ATP) in SCC7 and 4MOSC2 in a dose-dependent manner. The supernatant from irradiated cells upregulated the expression of PD-L1 in MDSCs. Mice treated with hypofractionated but not single-dose radiotherapy were resistant to tumour rechallenge by triggering ICD, when combined with anti-PD-L1 treatment. The therapeutic efficacy of combination treatment partially relies on MDSCs. The high expression of ICD markers was associated with activation of adaptive immune responses and a positive prognosis in HNSCC patients.
CONCLUSION
These results present a translatable method to substantially improve the antitumor immune response by combining PD-L1 blockade with immunogenic hypofractionated radiotherapy in HNSCC.
背景
提高免疫疗法的应答率将有助于癌症治疗的成功。在这里，我们旨在探索免疫原性放疗联合抗 PD-L1 治疗在免疫治疗抵抗的头颈部鳞状细胞癌（HNSCC）小鼠模型中的联合效应。
方法
体外照射 SCC7 和 4MOSC2 细胞系。用低分割或单次剂量放疗后给予抗 PD-L1 治疗来处理 SCC7 荷瘤小鼠。用抗 Gr-1 抗体耗竭髓系来源的抑制细胞（MDSCs）。收集人类样本以评估免疫细胞群和 ICD 标志物。
结果
照射以剂量依赖的方式增加 SCC7 和 4MOSC2 中免疫原性细胞死亡（ICD）标志物（钙网蛋白、HMGB1 和 ATP）的释放。照射细胞的上清液上调 MDSC 中 PD-L1 的表达。与单独放疗相比，低分割放疗联合抗 PD-L1 治疗可通过触发 ICD 来抵抗肿瘤再挑战，从而使小鼠产生放疗抵抗。联合治疗的疗效部分依赖于 MDSCs。ICD 标志物的高表达与适应性免疫反应的激活和 HNSCC 患者的良好预后相关。
结论
这些结果提供了一种可转化的方法，通过在 HNSCC 中联合 PD-L1 阻断和免疫原性低分割放疗，显著提高抗肿瘤免疫反应。
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