Details

Autor(en) / Beteiligte

• Reinhardt, Julia
• Landsberg, Jennifer
• Schmid-Burgk, Jonathan L
• Ramis, Bartomeu Bibiloni
• Bald, Tobias
• Glodde, Nicole
• Lopez-Ramos, Dorys
• Young, Arabella
• Ngiow, Shin Foong
• Nettersheim, Daniel
• Schorle, Hubert
• Quast, Thomas
• Kolanus, Waldemar
• Schadendorf, Dirk
• Long, Georgina V
• Madore, Jason
• Scolyer, Richard A
• Ribas, Antoni
• Smyth, Mark J
• Tumeh, Paul C
• Tüting, Thomas
• Hölzel, Michael

Titel

MAPK Signaling and Inflammation Link Melanoma Phenotype Switching to Induction of CD73 during Immunotherapy

Ist Teil von

• Cancer research (Chicago, Ill.), 2017-09, Vol.77 (17), p.4697-4709

Ort / Verlag

United States: American Association for Cancer Research, Inc

Erscheinungsjahr

2017

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• Evolution of tumor cell phenotypes promotes heterogeneity and therapy resistance. Here we found that induction of CD73, the enzyme that generates immunosuppressive adenosine, is linked to melanoma phenotype switching. Activating MAPK mutations and growth factors drove CD73 expression, which marked both nascent and full activation of a mesenchymal-like melanoma cell state program. Proinflammatory cytokines like TNFα cooperated with MAPK signaling through the c-Jun/AP-1 transcription factor complex to activate CD73 transcription by binding to an intronic enhancer. In a mouse model of T-cell immunotherapy, CD73 was induced in relapse melanomas, which acquired a mesenchymal-like phenotype. We also detected CD73 upregulation in melanoma patients progressing under adoptive T-cell transfer or immune checkpoint blockade, arguing for an adaptive resistance mechanism. Our work substantiates CD73 as a target to combine with current immunotherapies, but its dynamic regulation suggests limited value of CD73 pretreatment expression as a biomarker to stratify melanoma patients. .