A Bifunctional Antibody Targeting PD-1 and TGF-β Signaling Has Antitumor Activity in Combination with Radiotherapy and Attenuates Radiation-Induced Lung Injury
Sheng Wang, Duo Xu, Yuan Wang, Yuehua Zhou, Lingyan Xiao, Fang Li, Jingyao Tu, Wan Qin, Sidan Tian, Bolong Zheng, Yihua Wang, Xianglin Yuan, Yuanhui Liu, Bo Liu
Abstract
Radio-immunotherapy has antitumor activity but also causes toxicity, which limits its clinical application. JS-201 is a dual antibody targeting PD-1 and TGF-β signaling. We investigated the antitumor effect of JS-201 combined with radiotherapy (RT) and the effect on radiation-induced lung injury (RILI). Different tumor models were established to detect the antitumor effects of the combination of JS-201 and RT, and RILI models were established to observe the effects of JS-201. Transcriptome sequencing showed that JS-201 optimized the tumor microenvironment by inhibiting extracellular matrix formation and angiogenesis. Combining JS-201 with RT further increased the inflammatory response and immune infiltration and showed great abscopal effects in Lewis lung cancer luciferase-positive models. Single-cell sequencing demonstrated that JS-201 reduced fibroblast proliferation by inhibiting the TGF-β/Smad pathway and the release of neutrophil extracellular traps mediated by ROS, thereby relieving radiation-induced pulmonary fibrosis. In conclusion, the JS-201 and RT combination enhances antitumor effects while mitigating acute and chronic RILI, and it may have potential for translational investigation as a cancer treatment strategy.