Journal
NATURE MEDICINE
Volume 26, Issue 12, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41591-020-1073-3
Keywords
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Funding
- Spanish Ministry of Economy and Innovation [SAF2017-89533-R]
- Melanoma Research Alliance
- Worldwide Cancer Research
- Asociacion Espanola Contra el Cancer (AECC)
- Spanish Ministry of Health [AES-PIS PI18/1057]
- Fundacion BBVA-Becas Leonardo a Investigadores y Creadores Culturales 2018
- Fundacion 'La Caixa'
- AECC
- MINECO [SAF2013-45504-R]
- Ramon y Cajal Programme (MINECO) [RYC-2012-10651]
- Immutrain Marie Skodowska-Curie ITN Grant
- European Union's Horizon 2020 Research and Innovation Programme [641458]
- Fundacion 'La Caixa' Health Research 2019
- [PT13/0001]
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Tumor-secreted midkine modulates immune tolerance in the melanoma tumor microenvironment and determines resistance to immune checkpoint blockade. 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-kappa B 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.
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