Exosomal PVRL4 Promotes Lung Adenocarcinoma Progression by Enhancing the Generation of Myeloid-Derived Suppressor Cell-Secreted TGF-β1

Sep 21, 2026

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Exosomal PVRL4 is investigated as a driver of lung adenocarcinoma progression through immune suppression mediated by myeloid-derived suppressor cells (MDSCs). The study evaluates how PVRL4 affects LUAD cell proliferation, invasion, migration, and apoptosis, and how PVRL4 is packaged into exosomes and transferred to PBMCs to induce MDSCs. Mechanistic emphasis centers on MDSC-secreted TGF-β1 and its reversal by TGF-β1-overexpressed MDSCs.

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CategoryHealthcare

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Thoracic Cancer ORIGINAL ARTICLE OPEN ACCESS Exosomal PVRL4 Promotes Lung Adenocarcinoma Progression by Enhancing the Generation of Myeloid-Derived Suppressor Cell-Secreted TGF-β1 Yahai Liang1 | Jinmei Li1 | Lihua Zhang1 | Jinling Zhou2 | Meilian Liu1 | Xiaoxia Peng1 | Weizhen Zheng1 | Zhennan Lai1 1Department of Pulmonary Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China | 2Anesthesia Surgery Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China Correspondence: Zhennan Lai ([laizhenn@163.com](laizhenn@163.com)) Received: 20 August 2024 | Revised: 25 October 2024 | Accepted: 11 November 2024 Funding: The authors received no specific funding for this work. Keywords: exosome | immunosuppressive activity | LUAD | MDSCs | PBMCs | PVRL4 | TGF-β1 ABSTRACT Background: The cancer cell marker poliovirus receptor-like protein 4 (PVRL4) has been shown to be highly expressed in many cancers, including lung cancer. Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells with immunosuppressive roles that can attenuate the anticancer response. Here, the precise functions and the relationship between PVRL4 and MDSCs in lung adenocarcinoma (LUAD) progression were investigated. Methods: Detection of levels of mRNAs and proteins was conducted using qRT-PCR and western blotting. The CCK-8, colony formation, transwell, wound healing assays, and flow cytometry were used to explore cell growth, invasion, migration, and apoptosis, respectively. ELISA analysis detected TGF-β1 contents. LUAD mouse models were established for in vivo assay. Exosomes were isolated by ultracentrifugation. MDSCs were induced from peripheral blood mononuclear cells (PBMCs) by cytokine or co-culture with cancer cells. Results: LUAD tissues and cells showed high PVRL4 expression, and PVRL4 deficiency suppressed LUAD cell proliferation, invasion, migration, and induced cell apoptosis in vitro, and impeded LUAD growth in vivo. Thereafter, we found that PVRL4 was packaged into exosomes in LUAD cells, and could be transferred into PBMCs to promote MDSC induction and the expression of MDSC-secreted TGF-β1. Functionally, the silencing of exosomal PVRL4 impaired LUAD cell proliferation, invasion, migration, and evoked cell apoptosis, which could be reversed by the incubation ofTGF-β1-overexpressed MDSCs. Conclusion: Exosomal PVRL4 promoted LUAD progression by inducing the secretion ofTGF-β1 in MDSCs, indicating a novel direction for LUAD immunotherapy. 1 | Introduction Lung adenocarcinoma (LUAD) is one of the deadliest cancers accounting for about 40% of all lung cancer cases [1, 2] . The majority of LUAD are incurable or advanced, so the 5-year survival of LUAD patients is only 15%[3, 4] . Surgery remains the standard therapy yet; however, there is a high risk of relapse [5] . Thus, a better understanding of the pathogenesis of LUAD is indispensable for developing effective therapeutic strategies for this disease. In recent years, molecular targeted therapy using therapeutic monoclonal antibodies or small molecule agents to impact signal transduction has been recognized to play a fundamental role in precision medicine for oncotherapy [6, 7]. The achievement of anticancer effects of molecular targeted therapy is involved in This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2024 The Author(s) . Thoracic Cancer published by John Wiley & Sons Australia, Ltd. Thoracic Cancer, 2025; 16:e15495 1 of 11 [https://doi.org/10.1111/1759-7714.15495](https://doi.org/10.1111/1759-7714.15495) diverse mechanisms, including the suppression of cell angiogenesis, growth, and metastasis, the promotion of cell apoptosis, the enhancement antitumor

FAQs

What role does exosomal PVRL4 play in LUAD progression?

Exosomal PVRL4 promotes LUAD progression by enhancing the generation of MDSCs and increasing MDSC-secreted TGF-β1.

How do the experiments assess the effect of PVRL4 on LUAD cells?

The study uses qRT-PCR and western blotting for mRNA/protein levels, and CCK-8, colony formation, transwell, wound healing, flow cytometry, and ELISA to evaluate growth, invasion, migration, apoptosis, and TGF-β1 content.

How is the mechanism involving TGF-β1 tested?

Silencing exosomal PVRL4 impairs LUAD malignant phenotypes, and these effects can be reversed by incubation with TGF-β1-overexpressed MDSCs.

Sep 21, 2026

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