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Mitochondria Energy Metabolism Depression as Novel Adjuvant to Sensitize Radiotherapy and Inhibit Radiation Induced-Pulmonary Fibrosis.

ABSTRACT: Currently, the typical combination therapy of programmed death ligand-1 (PD-L1) antibodies with radiotherapy (RT) still exhibits impaired immunogenic antitumor response in clinical due to lessened DNA damage and acquired immune tolerance via the upregulation of some other immune checkpoint inhibitors. Apart from this, such combination therapy may raise the occurrence rate of radiation-induced lung fibrosis (RIPF) due to enhanced systemic inflammation, leading to the ultimate death of cancer patients (average survival time of about 3 years). Therefore, it is newly revealed that mitochondria energy metabolism regulation can be used as a novel effective PD-L1 and transforming growth factor-β (TGF-β) dual-downregulation method. Following this, IR-TAM is prepared by conjugating mitochondria-targeted heptamethine cyanine dye IR-68 with oxidative phosphorylation (OXPHOS) inhibitor Tamoxifen (TAM), which then self-assembled with albumin (Alb) to form IR-TAM@Alb nanoparticles. By doing this, tumor-targeting IR-TAM@Alb nanoparticle effectively reversed tumor hypoxia and depressed PD-L1 and TGF-β expression to sensitize RT. Meanwhile, due to the capacity of heptamethine cyanine dye in targeting RIPF and the function of TAM in depressing TGF-β, IR-TAM@Alb also ameliorated fibrosis development induced by RT.

SUBMITTER: Zhou Z

PROVIDER: S-EPMC11234447 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Mitochondria Energy Metabolism Depression as Novel Adjuvant to Sensitize Radiotherapy and Inhibit Radiation Induced-Pulmonary Fibrosis.

Zhou Zaigang Z Jiang Xin X Yi Lei L Li Cheng C Wang Haoxiang H Xiong Wei W Li Zhipeng Z Shen Jianliang J

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20240507 26

Currently, the typical combination therapy of programmed death ligand-1 (PD-L1) antibodies with radiotherapy (RT) still exhibits impaired immunogenic antitumor response in clinical due to lessened DNA damage and acquired immune tolerance via the upregulation of some other immune checkpoint inhibitors. Apart from this, such combination therapy may raise the occurrence rate of radiation-induced lung fibrosis (RIPF) due to enhanced systemic inflammation, leading to the ultimate death of cancer pati ...[more]

PMID: 38715382

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Project description:BackgroundDespite 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.MethodsThe 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.ResultsRT 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.ConclusionsOur 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.

Dataset Information

Mitochondria Energy Metabolism Depression as Novel Adjuvant to Sensitize Radiotherapy and Inhibit Radiation Induced-Pulmonary Fibrosis.

Publications

Mitochondria Energy Metabolism Depression as Novel Adjuvant to Sensitize Radiotherapy and Inhibit Radiation Induced-Pulmonary Fibrosis.

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