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STING agonist enhances the efficacy of programmed death-ligand 1 monoclonal antibody in breast cancer immunotherapy by activating the interferon-β signalling pathway.

ABSTRACT: This study aimed to explore the role of a stimulator of interferon (IFN) gene (STING) agonist in breast cancer (BCa) immunotherapy. Clinical samples were collected from 37 patients with BCa. A tumor-bearing mouse model was established by injecting 4T1 cells into the mammary fat pad of mice. STING agonist and atezolizumab were injected in the mice twice a week for 2 weeks. Peripheral blood, tumor mass, lung, liver, brain cortex and kidney samples of the tumor-bearing mice were collected. Anti-IFN alpha receptor subunit 1 (IFNAR1) was used to treat 4T1 cells. Tumor tissues of patients with BCa exhibited lower STING and high programmed cell death protein 1 and programmed death-ligand 1 protein expressions. The STING agonist inhibited 4T1 cell growth in mice (P < 0.001) and increased the IFN-β level and phosphorylation of STING, TBK1, IRF3 and STAT1 in tumor mass of tumor-bearing mice (P < 0.001). It synergized with atezolizumab to inhibit 4T1 cell growth in mice and increased tumor necrosis factor-α, IFN-β, interleukin-10 and IFN-γ levels in the peripheral blood and tumor mass (P < 0.01). It synergized with atezolizumab to increase CD8+ cytotoxic T cells and decrease FOXP3+ Treg cells in the tumor-bearing mouse model. The STING agonist was nontoxic to the lung, liver, brain cortex and kidney. Anti-IFNAR1 reversed the STING agonist promotion on TBK1, IRF3 and STAT1 phosphorylation in 4T1 cells (P < 0.01). STING agonists enhance the efficacy of atezolizumab in BCa immunotherapy by activating the IFN-β signaling pathway.

SUBMITTER: Yin M

PROVIDER: S-EPMC8973354 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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STING agonist enhances the efficacy of programmed death-ligand 1 monoclonal antibody in breast cancer immunotherapy by activating the interferon-β signalling pathway.

Yin Mingming M Hu Jinlong J Yuan Zhongxu Z Luo Guangyi G Yao Jiaming J Wang Rundong R Liu Dongquan D Cao Baoqiang B Wu Wenyong W Hu Zhiqi Z

Cell cycle (Georgetown, Tex.) 20220207 8

This study aimed to explore the role of a stimulator of interferon (IFN) gene (STING) agonist in breast cancer (BCa) immunotherapy. Clinical samples were collected from 37 patients with BCa. A tumor-bearing mouse model was established by injecting 4T1 cells into the mammary fat pad of mice. STING agonist and atezolizumab were injected in the mice twice a week for 2 weeks. Peripheral blood, tumor mass, lung, liver, brain cortex and kidney samples of the tumor-bearing mice were collected. Anti-IFN ...[more]

PMID: 35130108

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Project description:IntroductionThe clinical successes seen with anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-[L]1) agents have galvanized the field of immuno-oncology. We evaluated the landscape and trends in immunotherapy trials involving the PD-(L)1 axis in intrathoracic tumors.MethodsWe identified clinical trials involving anti-PD-(L)1 agents on the ClinicalTrials.gov registry through November 13, 2020 for NSCLC, SCLC, mesothelioma, and thymic epithelial tumor. Clinical trials were indexed according to monotherapy versus combination approaches, PD-(L)1 agents under investigation, clinical settings, trial start date, and partner drug(s). We assessed redundancy among the clinical trials.ResultsWe found 686 clinical trials investigating anti-PD-(L)1 agents for intrathoracic tumors (540 trials in NSCLC, 96 in SCLC, 38 in mesothelioma, and 12 in thymic epithelial tumor). A total of 23 PD-(L)1 inhibitors are undergoing clinical development. A total of 81% of trials assess combination treatment. The number of clinical trials has been growing exponentially in the past decade. PD-(L)1 blockade was frequently combined with chemotherapy or immunomodulatory therapy. Various strategies are in development to overcome resistance to PD-(L)1 blockade in metastatic NSCLC. PD-(L)1 blockade is also increasingly evaluated in neoadjuvant and adjuvant settings. After the U.S. Food and Drug Administration's approval of an anti-PD-(L)1 agent for a specific indication, 14 trials were launched thereafter, which continued to randomize patients to treatments that were inferior to the best available therapy.ConclusionsThe number of clinical trials investigating anti-PD-(L)1 agents in intrathoracic tumors has experienced a steep increase over the past decade with a notable upward trend for combination trials. To reduce duplicative research efforts and accelerate the development of effective immunotherapeutics, improved coordination among key stakeholders and the adoption of innovative trial designs will be vital.

Dataset Information

STING agonist enhances the efficacy of programmed death-ligand 1 monoclonal antibody in breast cancer immunotherapy by activating the interferon-β signalling pathway.

Publications

STING agonist enhances the efficacy of programmed death-ligand 1 monoclonal antibody in breast cancer immunotherapy by activating the interferon-β signalling pathway.

Similar Datasets

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