Journal Article

Anti-TGF-β/PD-L1 bispecific antibody synergizes with radiotherapy to enhance antitumor immunity and mitigate radiation-induced pulmonary fibrosis

Zhang, Jing, Guo, Yarong, Chu, Qian, Yan, Yuheng, Wu, Kongming, Wu, Yuze, Mei, Qi, Zhou, Binghan, Yi, Ming, Zhou, Pengfei, Niu, Mengke

2025

Overview

Background Despite the success of immune checkpoint inhibitors (ICIs) in multiple malignant tumors, a significant proportion of patients remain unresponsive to treatment. Radiotherapy (RT) elicits immunogenic antitumor responses but concurrently activates several immune evasion mechanisms. Our earlier research demonstrated the efficacy of YM101, an anti-TGF-β/PD-L1 bispecific antibody, in stroma-rich tumors. Nevertheless, YM101 has demonstrated reduced effectiveness in non-inflamed tumors characterized by poor immune cell infiltration. This study investigated the potential synergy between RT and YM101 in overcoming immunotherapy resistance and mitigating RT-induced pulmonary fibrosis. Methods The antitumor activity and survival outcomes of RT plus YM101 treatment in vivo were explored in several non-inflamed murine tumor models. Furthermore, the inhibition of pulmonary metastases was assessed in a pulmonary metastasis model. The impact of RT on dendritic cell (DC) maturation was quantified by flow cytometry, whereas cytokine and chemokine secretions were measured by ELISA. To comprehensively characterize changes in the tumor microenvironment, we utilized a combination of methods, including flow cytometry, IHC staining, multiplex inmunofluorecence and RNA sequencing. Additionally, we evaluated the impact of YM101 on RT-induced pulmonary fibrosis. Results RT plus YM101 significantly inhibited tumor growth, prolonged survival and inhibited pulmonary metastases compared with monotherapies in non-inflamed tumors with poor immune infiltration. RT promoted DC maturation in a dose-dependent manner and increased the secretions of multiple proinflammatory cytokines. Mechanistically, RT plus YM101 simultaneously increased the infiltration and activation of intratumoral DCs and tumor-infiltrating lymphocytes and reshaped the tumor microenvironment landscape. Notably, YM101 attenuated both RT-induced peritumoral fibrosis and pulmonary fibrosis. Conclusions Our findings suggest that RT combined with YM101 enhances antitumor immunity and overcomes resistance in non-inflamed tumors in preclinical models, while simultaneously showing potential in mitigating RT-induced fibrosis. This combination therapy demonstrates promise in overcoming ICI resistance, while potentially sparing normal pulmonary tissue, thereby providing a strong rationale for further clinical investigations.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Animal models / Animals / Antibodies / Antibodies, Bispecific - pharmacology / Antibodies, Bispecific - therapeutic use / Antitumor activity / B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - immunology / Bispecific antibodies / Bispecific antibody / Cancer Research / Cancer therapies / Cell Line, Tumor / Cells / Chemokines / Cytokines / Dendritic cells / Enzyme-linked immunosorbent assay / Experiments / Female / Fibrosis / Flow cytometry / Hematology / Humans / Immune checkpoint inhibitors / Immunity / Immunogenicity / Immunotherapy / Infiltration / Inflammation / Laboratories / Lung diseases / Lung Neoplasms - radiotherapy / Lung Neoplasms - secondary / Lung Neoplasms - therapy / Lungs / Lymphocytes / Maturation / Medicine / Medicine & Public Health / Metastases / Metastasis / Mice / Mice, Inbred C57BL / Oncology / PD-L1 / PD-L1 protein / Pulmonary fibrosis / Pulmonary Fibrosis - etiology / Radiation therapy / Radiotherapy / Secretions / Stroma / Survival analysis / TGF-β / Transforming Growth Factor beta - antagonists & inhibitors / Transforming Growth Factor beta - immunology / Transforming growth factor-b / Tumor microenvironment / Tumor Microenvironment - drug effects / Tumors