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

被引：2

作者：

Catena, Xavier ^{[1
]}

Contreras-Alcalde, Marta ^{[1
]}

Juan-Larrea, Naiara ^{[1
]}

Cerezo-Wallis, Daniela ^{[1
,8
]}

Calvo, Tonantzin G. ^{[1
]}

Mucientes, Cynthia ^{[1
]}

Olmeda, David ^{[1
,9
]}

Suarez, Javier ^{[1
]}

Oterino-Sogo, Sergio ^{[1
]}

Martinez, Lola ^{[2
]}

Megias, Diego ^{[3
]}

Sancho, David ^{[4
]}

Tejedo, Cristina ^{[1
]}

Frago, Susana ^{[1
]}

Dudziak, Diana ^{[5
,6
]}

Seretis, Athanasios ^{[7
]}

Stoitzner, Patrizia ^{[7
]}

Soengas, Maria S. ^{[1
]}

机构：

[1] Spanish Natl Canc Res Ctr CNIO, Mol Oncol Programme, Melanoma Lab, Madrid, Spain

[2] Spanish Natl Canc Res Ctr CNIO, Biotechnol Programme, Flow Cytometry Core Unit, Madrid, Spain

[3] Inst salud Carlos ISCIII 3, Adv Opt Microscopy unit, Majadahonda, Spain

[4] Ctr Nacl Invest Cardiovasc CN, Immunobiol Lab, Madrid, Spain

[5] Friedrich Schiller Univ, Jena Univ Hosp, Inst Immunol, Jena, Germany

[6] Comprehens Canc Ctr Cent Germany Jena Leipzig, Jena, Germany

[7] Med Univ Innsbruck, Dept Dermatol Venereol & Allergol, Innsbruck, Austria

[8] Yale Univ, Sch Med, New Haven, CT USA

[9] Inst Invest Biomed Sols Morreale, Madrid, Spain

来源：

NATURE CANCER | 2025年 / 6卷 / 04期

基金：

欧洲研究理事会;

关键词：

CLINICAL-RESPONSE; THERAPY; GENERATION; RESISTANCE; REVEALS; CD8(+); CDC1;

D O I：

10.1038/s43018-025-00929-y

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：682 / 701

页数：44

共 24 条

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