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oai:repisalud.isciii.es:20.500.12105/174242024-11-29T15:55:41Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Cerezo-Wallis, Daniela author Contreras-Alcalde, Marta author Troulé, Kevin author Catena, Xavier author Mucientes, Cynthia author Calvo, Tonantzin G author Cañón, Estela author Tejedo, Cristina author Pennacchi, Paula C author Hogan, Sabrina author Kölblinger, Peter author Tejero, Héctor author Chen, Andrew X author Ibarz, Nuria author Graña-Castro, Osvaldo author Martinez Garcia, Maria Dolores author Muñoz, Javier author Ortiz-Romero, Pablo author Rodriguez-Peralto, José L author Gómez-López, Gonzalo author Al-Shahrour, Fatima author Rabadán, Raúl author Levesque, Mitchell P author Olmeda, David author Soengas, MS author 2020-12 An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8+ T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas. Nat Med . 2020;26(12):1865-1877 10.1038/s41591-020-1073-3 1546-170X Nature medicine 33077955 http://hdl.handle.net/20.500.12105/17424 Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state.