Li Yao, Long Yaping, Ge Xiangwei, Zhang Pengfei, Li Tao, Wu Liangliang, Fan Hao, Du Zhijuan, Liu Qiaowei, Hu Yi
Medical School of Chinese People's Liberation Army (PLA), Beijing 100000, China.
Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100000, China.
Vaccines (Basel). 2024 Dec 14;12(12):1412. doi: 10.3390/vaccines12121412.
Combining radiotherapy with targeted therapy benefits patients with advanced epidermal growth factor receptor-mutated non-small cell lung cancer (EGFRm NSCLC). However, the optimal strategy to combine EGFR tyrosine kinase inhibitors (TKIs) with radiotherapy for maximum efficacy and minimal toxicity is still uncertain. Notably, EVs, which serve as communication mediators among tumor cells, play a crucial role in the anti-tumor immune response. Methods To exploit the role of EVs in the delivery of tumor antigens, we formulated a therapeutic strategy that involves the use of radiation-induced tumor-derived EVs (TEXs) loaded onto dendritic cells (DCs) as a kind of vaccine in conjunction with EGFR TKIs and assessed the efficacy and safety of this approach in the treatment of EGFRm NSCLC. Results In our study, we characterized the release of immunogens as influenced by various modes of cell death, examining the impact of different levels of cell death under diverse irradiation modalities. Our results demonstrated that a radiation mode of 6Gy3f exhibited the most promising potential to stimulate anti-tumor immune responses. This radiotherapy fraction, combined with TKIs, showed promising results in a tumor-bearing mouse model with an EGFR mutation, although there is a risk of radiation-associated pneumonitis. Furthermore, we found that 6Gy3f-TEXs in vitro activate DCs and promote T cell proliferation as well as cytotoxic T lymphocyte-mediated tumor cell destruction. The administration of EGFR-TKIs combined DCs loaded with 6Gy*3f-TEXs exhibited the potential to inhibit tumor growth and mitigate the risk of pneumonitis. Together, the research shows that TEXs from high-dose fractionation radiation can mature DCs and boost the killing of cytotoxic T lymphocytes. Combining these DC vaccines with Osimertinib offers a promising and safe treatment for EGFRm NSCLC.
将放射治疗与靶向治疗相结合对晚期表皮生长因子受体突变的非小细胞肺癌（EGFRm NSCLC）患者有益。然而，将EGFR酪氨酸激酶抑制剂（TKIs）与放射治疗相结合以实现最大疗效和最小毒性的最佳策略仍不确定。值得注意的是，细胞外囊泡（EVs）作为肿瘤细胞间的通讯介质，在抗肿瘤免疫反应中起关键作用。方法 为了探究EVs在肿瘤抗原递送中的作用，我们制定了一种治疗策略，即使用负载于树突状细胞（DCs）上的辐射诱导肿瘤来源的细胞外囊泡（TEXs）作为一种疫苗，联合EGFR TKIs，并评估该方法治疗EGFRm NSCLC的疗效和安全性。结果 在我们的研究中，我们表征了受各种细胞死亡模式影响的免疫原释放情况，研究了不同照射方式下不同程度细胞死亡的影响。我们的结果表明，6Gy3f的放射模式在刺激抗肿瘤免疫反应方面显示出最有前景的潜力。这种放疗分割方案与TKIs联合，在携带EGFR突变的荷瘤小鼠模型中显示出有前景的结果，尽管存在放射性肺炎的风险。此外，我们发现体外6Gy3f-TEXs可激活DCs并促进T细胞增殖以及细胞毒性T淋巴细胞介导的肿瘤细胞破坏。给予EGFR-TKIs联合负载6Gy*3f-TEXs的DCs具有抑制肿瘤生长和降低肺炎风险的潜力。总之，研究表明高剂量分割放疗产生的TEXs可使DCs成熟并增强细胞毒性T淋巴细胞的杀伤作用。将这些DC疫苗与奥希替尼联合为EGFRm NSCLC提供了一种有前景且安全有效的治疗方法。
