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

Cancer Res. 2017 Sep 1;77(17):4697-4709. doi: 10.1158/0008-5472.CAN-17-0395. Epub 2017 Jun 26.

Abstract

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. Cancer Res; 77(17); 4697-709. ©2017 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase / metabolism*
  • Adenosine / metabolism
  • Adoptive Transfer
  • Animals
  • GPI-Linked Proteins / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunotherapy*
  • Inflammation / complications*
  • Inflammation / pathology
  • Melanoma / immunology
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Melanoma / therapy
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Neoplasm Invasiveness
  • Prognosis
  • Retrospective Studies
  • T-Lymphocytes / transplantation*
  • Transcription Factor AP-1 / metabolism
  • Tumor Cells, Cultured

Substances

  • GPI-Linked Proteins
  • Transcription Factor AP-1
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • 5'-Nucleotidase
  • NT5E protein, human
  • Adenosine