Key Laboratory for Electromagnetic Radiation Medical Protection of Ministry of Education, Army Medical University, Chongqing, 400038, China.
Department of Occupational Health, College of Preventive Medicine, Army Medical University, Chongqing, 400038, China.
Acta Pharmacol Sin. 2024 Jul;45(7):1492-1505. doi: 10.1038/s41401-024-01260-5. Epub 2024 Mar 27.
Immunosuppression by the tumor microenvironment is a pivotal factor contributing to tumor progression and immunotherapy resistance. Priming the tumor immune microenvironment (TIME) has emerged as a promising strategy for improving the efficacy of cancer immunotherapy. In this study we investigated the effects of noninvasive radiofrequency radiation (RFR) exposure on tumor progression and TIME phenotype, as well as the antitumor potential of PD-1 blockage in a model of pulmonary metastatic melanoma (PMM). Mouse model of PMM was established by tail vein injection of B16F10 cells. From day 3 after injection, the mice were exposed to RFR at an average specific absorption rate of 9.7 W/kg for 1 h per day for 14 days. After RFR exposure, lung tissues were harvested and RNAs were extracted for transcriptome sequencing; PMM-infiltrating immune cells were isolated for single-cell RNA-seq analysis. We showed that RFR exposure significantly impeded PMM progression accompanied by remodeled TIME of PMM via altering the proportion and transcription profile of tumor-infiltrating immune cells. RFR exposure increased the activation and cytotoxicity signatures of tumor-infiltrating CD8 T cells, particularly in the early activation subset with upregulated genes associated with T cell cytotoxicity. The PD-1 checkpoint pathway was upregulated by RFR exposure in CD8 T cells. RFR exposure also augmented NK cell subsets with increased cytotoxic characteristics in PMM. RFR exposure enhanced the effector function of tumor-infiltrating CD8 T cells and NK cells, evidenced by increased expression of cytotoxic molecules. RFR-induced inhibition of PMM growth was mediated by RFR-activated CD8 T cells and NK cells. We conclude that noninvasive RFR exposure induces antitumor remodeling of the TIME, leading to inhibition of tumor progression, which provides a promising novel strategy for TIME priming and potential combination with cancer immunotherapy.
肿瘤微环境的免疫抑制是促进肿瘤进展和免疫治疗耐药的关键因素。 肿瘤免疫微环境（TIME）的启动已成为提高癌症免疫治疗疗效的有前途的策略。 在这项研究中，我们研究了非侵入性射频辐射（RFR）暴露对肿瘤进展和 TIME 表型的影响，以及 PD-1 阻断在肺转移性黑色素瘤（PMM）模型中的抗肿瘤潜力。 通过尾静脉注射 B16F10 细胞建立小鼠 PMM 模型。 从注射后第 3 天开始，每天将小鼠以平均比吸收率 9.7 W/kg 暴露于 RFR 1 小时，持续 14 天。 RFR 暴露后，收获肺组织并提取 RNA 进行转录组测序；分离 PMM 浸润免疫细胞进行单细胞 RNA-seq 分析。 我们表明，RFR 暴露通过改变肿瘤浸润免疫细胞的比例和转录谱，显著阻碍 PMM 的进展，并重塑 PMM 的 TIME。 RFR 暴露增加了肿瘤浸润 CD8 T 细胞的激活和细胞毒性特征，尤其是在早期激活亚群中，与 T 细胞细胞毒性相关的基因上调。 CD8 T 细胞中 RFR 暴露上调了 PD-1 检查点途径。 RFR 暴露还增加了 PMM 中具有增加的细胞毒性特征的 NK 细胞亚群。 RFR 暴露增强了肿瘤浸润 CD8 T 细胞和 NK 细胞的效应功能，表现为细胞毒性分子的表达增加。 RFR 诱导的 PMM 生长抑制是由 RFR 激活的 CD8 T 细胞和 NK 细胞介导的。 我们得出结论，非侵入性 RFR 暴露诱导 TIME 的抗肿瘤重塑，导致肿瘤进展抑制，为 TIME 启动提供了有前途的新策略，并可能与癌症免疫治疗相结合。
