Systemic rewiring of dendritic cells by melanoma-secreted midkine impairs immune surveillance and response to immune checkpoint blockade.

IF 23.5 1区医学 Q1 ONCOLOGY

Nature cancer Pub Date : 2025-03-28 DOI:10.1038/s43018-025-00929-y

Xavier Catena, Marta Contreras-Alcalde, Naiara Juan-Larrea, Daniela Cerezo-Wallis, Tonantzin G Calvo, Cynthia Mucientes, David Olmeda, Javier Suárez, Sergio Oterino-Sogo, Lola Martínez, Diego Megías, David Sancho, Cristina Tejedo, Susana Frago, Diana Dudziak, Athanasios Seretis, Patrizia Stoitzner, María S Soengas

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Abstract

Cutaneous melanomas express a high number of potential neoepitopes, yet a substantial fraction of melanomas shift into immunologically cold phenotypes. Using cellular systems, mouse models and large datasets, we identify the tumor-secreted growth factor midkine (MDK) as a multilayered inhibitor of antigen-presenting cells. Mechanistically, MDK acts systemically in primary tumors, lymph nodes and the bone marrow, promoting a STAT3-mediated impairment of differentiation, activation and function of dendritic cells (DCs), particularly, conventional type 1 DCs (cDC1s). Furthermore, MDK rewires DCs toward a tolerogenic state, impairing CD8⁺ T cell activation. Downregulating MDK improves DC-targeted vaccination, CD40 agonist treatment and immune checkpoint blockade in mouse models. Moreover, we present an MDK-associated signature in DCs that defines poor prognosis and immune checkpoint blockade resistance in individuals with cancer. An inverse correlation between MDK- and cDC1-associated signatures was observed in a variety of tumor types, broadening the therapeutic implications of MDK in immune-refractory malignancies.

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黑素瘤分泌的中间因子对树突状细胞的系统性重新布线损害了免疫监视和对免疫检查点封锁的反应。

皮肤黑色素瘤表达大量潜在的新表位，但相当一部分黑色素瘤转变为免疫冷表型。利用细胞系统、小鼠模型和大型数据集，我们确定肿瘤分泌生长因子midkine （MDK）是抗原呈递细胞的多层抑制剂。从机制上讲，MDK在原发性肿瘤、淋巴结和骨髓中系统性地起作用，促进stat3介导的树突状细胞（DCs）分化、激活和功能的损伤，特别是传统的1型树突状细胞（cDC1s）。此外，MDK将dc重新连接到耐受状态，从而损害CD8+ T细胞的激活。在小鼠模型中，下调MDK可改善dc靶向疫苗接种、CD40激动剂治疗和免疫检查点阻断。此外，我们在dc中提出了mdk相关的特征，该特征定义了癌症患者的预后不良和免疫检查点阻断抵抗。在多种肿瘤类型中观察到MDK-和cdc1相关特征之间的负相关，扩大了MDK在免疫难治性恶性肿瘤中的治疗意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature cancer Medicine-Oncology

CiteScore

31.10

自引率

1.80%

发文量

129

期刊介绍： Cancer is a devastating disease responsible for millions of deaths worldwide. However, many of these deaths could be prevented with improved prevention and treatment strategies. To achieve this, it is crucial to focus on accurate diagnosis, effective treatment methods, and understanding the socioeconomic factors that influence cancer rates. Nature Cancer aims to serve as a unique platform for sharing the latest advancements in cancer research across various scientific fields, encompassing life sciences, physical sciences, applied sciences, and social sciences. The journal is particularly interested in fundamental research that enhances our understanding of tumor development and progression, as well as research that translates this knowledge into clinical applications through innovative diagnostic and therapeutic approaches. Additionally, Nature Cancer welcomes clinical studies that inform cancer diagnosis, treatment, and prevention, along with contributions exploring the societal impact of cancer on a global scale. In addition to publishing original research, Nature Cancer will feature Comments, Reviews, News & Views, Features, and Correspondence that hold significant value for the diverse field of cancer research.