LAMTOR1 decreased exosomal PD-L1 to enhance immunotherapy efficacy in non-small cell lung cancer

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cancer Pub Date : 2024-09-02 DOI:10.1186/s12943-024-02099-4
Bo Wu, Xin Huang, Xiang Shi, Meixi Jiang, Hongxu Liu, Li Zhao
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Abstract

Great progress has been made in utilizing immune checkpoint blockade (ICB) for the treatment of non-small-cell lung cancer (NSCLC). Therapies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1, expressed on tumor cells, have demonstrated potential in improving patient survival rates. An unresolved issue involves immune suppression induced by exosomal PD-L1 within the tumor microenvironment (TME), particularly regarding CD8+ T cells. Our study unveiled the crucial involvement of LAMTOR1 in suppressing the exosomes of PD-L1 and promoting CD8+ T cell infiltration in NSCLC. Through its interaction with HRS, LAMTOR1 facilitates PD-L1 lysosomal degradation, thereby reducing exosomal PD-L1 release. Notably, the ability of LAMTOR1 to promote PD-L1 lysosomal degradation relies on a specific ubiquitination site and an HRS binding sequence. The findings suggest that employing LAMTOR1 to construct peptides could serve as a promising strategy for bolstering the efficacy of immunotherapy in NSCLC. The discovery and comprehension of how LAMTOR1 inhibits the release of exosomal PD-L1 offer insights into potential therapeutic strategies for improving immunotherapy. It is imperative to conduct further research and clinical trials to investigate the feasibility and efficacy of targeting LAMTOR1 in NSCLC treatment.
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LAMTOR1 可减少外泌体 PD-L1,从而提高非小细胞肺癌的免疫疗法疗效
利用免疫检查点阻断疗法(ICB)治疗非小细胞肺癌(NSCLC)已取得了巨大进展。针对肿瘤细胞上表达的程序性细胞死亡蛋白 1(PD-1)及其配体 PD-L1 的疗法在提高患者生存率方面已显示出潜力。一个悬而未决的问题涉及肿瘤微环境(TME)中外泌体 PD-L1 诱导的免疫抑制,尤其是对 CD8+ T 细胞的抑制。我们的研究揭示了LAMTOR1在抑制PD-L1外泌体和促进CD8+ T细胞浸润NSCLC中的关键作用。通过与HRS相互作用,LAMTOR1促进了PD-L1溶酶体降解,从而减少了PD-L1外泌体的释放。值得注意的是,LAMTOR1促进PD-L1溶酶体降解的能力依赖于一个特定的泛素化位点和一个HRS结合序列。研究结果表明,利用 LAMTOR1 构建多肽可能是提高 NSCLC 免疫疗法疗效的有效策略。发现和理解LAMTOR1如何抑制外泌体PD-L1的释放为改进免疫疗法的潜在治疗策略提供了启示。当务之急是开展进一步的研究和临床试验,以调查靶向 LAMTOR1 在 NSCLC 治疗中的可行性和疗效。
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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